Therapeutic compounds

Abstract

The present invention relates to compounds that are MALT1 inhibitors. The compounds have the structural formula I defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with MALT1.

Description

THERAPEUTIC COMPOUNDSINTRODUCTION

[0001] The present invention relates to compounds that are MALT1 inhibitors. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with MALT1.BACKGROUND OF THE INVENTION

[0002] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular protein which plays a key role in antigen receptor-induced NF-kB pathway activation in T and B lymphocytes, via both a scaffolding function and a protease function. Antigen receptor triggering leads to formation of the CBM complex, comprising a CARMA or CARD protein, BCL10 and MALT1 , that subsequently acts as a scaffold to recruit the ubiquitin ligase TRAF6 and the kinases TAK1 and IKK. This leads to NF-kB activation through IKK-dependent phosphorylation and proteasomal degradation of the NF-kB inhibitor IkB, allowing NF-kB to translate to the nucleus and initiate transcription of target genes (doi.org / 10.1038 / ni1568; doi:10.1007 / s00018-015-2059-z). Additionally, MALT1 proteolytically cleaves a variety of substrates involved in NF-kB pathway regulation, including RelB, A20, CYLD, regnase-1 , HOIL, BCL10 and NIK; as well as autoproteolytic cleavage (doi: 10.1016 / j. biochi.2015.09.018). The overall effect of these cleavage events is thought to be expansion of the amplitude and duration of the NF-kB response (doi: 10.1016 / j. biochi.2015.09.018).

[0003] Several lines of genetic evidence suggest a key role of MALT 1 in the immune response. Mice lacking MALT1 protein were viable, but showed impairment in the generation and activation of Treg cells and less activated T cells in the periphery. MALT1 KO mice were protected in inflammatory models for MS (EAE) and rheumatoid arthritis (doi: 10.4049 / jimmunol.1201351). Mice expressing proteolytically inactive MALT1 show defects in multiple immune cell types including mature T- and B- cells and Treg cells, and develop progressive multiorgan inflammatory pathology (doi: 10.4049 / jimmunol.1402254; doi: 10.3389 / fimmu.2020.00745). A small cohort of human patients with defective MALT1 expression and / or function have presented with combined immunodeficiency (doi:10.1007 / s10875-014-0125-1 ; doi: 10.1016 / j.jaci.2013.04.047).

[0004] The highly aggressive activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is dependent on NF-kB activation via constitutive activation of theCARMA1-BCL10-MALT1 pathway for its survival and proliferation (doi.org / 10.1038 / nature04687). This constitutive NF-kB activation occurs often due to a variety of oncogenic mutations in pathway genes, including CARD11 , MYD88, CD79A / B and A20 (doi:10.1038 / nature07968; doi:10.1016 / j.ccr.2012.11.003). Pre-clinical studies have suggested that MALT 1 protease inhibition may be an effective treatment rationale for ABC-DLBCL, as treatment with the MALT1 inhibitor z-VRPR-fmk decreased the expression of NF-kB target genes with concomitant reduction in cell growth and viability (doi:10.1073 / pnas.0907511106; doi:10.1084 / jem.20091167), and small-molecule MALT1 inhibitors have also been shown to be active in xenograft models of ABC-DLBCL (doi:10.1016 / j.ccr.2012.11.002; doi:10.1016 / j.ccr.2012.11.003). Chronic activation of the BCR-mediated CBM-NF-kB pathway has been identified in a subset of mantle cell lymphoma (MCL) lines, suggesting that a subset of MCL may also be responsive to MALT 1 inhibition (doi:10.1038 / nm.3435). In MALT lymphoma (a type of non-Hodgkin lymphoma (NHL), the fusion protein CIAP2-MALT1 leads to constitutive activation of the NF-kB pathway, and these patients may also benefit from treatment with MALT1 inhibitors (doi 10.1074 / jbc.M605116200). MALT 1 inhibition may play a role in the treatment of some solid tumour types such as glioblastoma, breast cancer, melanoma, lung cancer, prostate cancer, pancreatic cancer and osteosarcoma (doi: 10.1038 / s41388-019-0958-4; doi:10.15252 / embj.2019102030; doi: 10.1111 / jcmm.15383; doi:10.1038 / oncsis.2017.68; doi: 10.1038 / onc.2015.146; doi: 10.3390 / biomedicines9030250; doi: 10.1002 / ijc.32567).

[0005] BTK inhibitors such as ibrutinib are important therapies for cancers such as MCL and chronic lymphocytic leukemia (CLL), but effectiveness is limited due to primary or acquired resistance (doi: 10.3390 / cancersl 2051328). MALT1 sits downstream of BTK in the NF-kB activation pathway and therefore may be an effective target either in combination with BTK inhibitors, or in BTKi-refractive tumours. MALT 1 has been shown to be constitutively active in CLL cell lines and treatment with the MALT-1 inhibitor MI-2 is effective against both naive and ibrutinib-resistant cell lines (doi: 10.1158 / 0008-5472. CAN- 17-2485). MALT1 inhibition has also been shown to be synergistic with the mTORCI inhibitor, rapamycin, in ABC-DLBCL cell lines, PDX and in vivo models, opening further possibilities for combination treatment and mitigation strategies for MALTIi resistance (doi: 10.1182 / blood.2019004713). Combinations of MALT1 inhibitors together with inhibitors of the Bcl-2 family protein have also been demonstrated to show a synergistic benefit in animal models of B-cell lymphoma (W02023 / 016995).

[0006] MALT 1 inhibitors have also been proposed to be effective therapies for a range of cancers, independent of dysregulation of the NF-kB pathway, as an immunomodulatory therapy (doi:10.1038 / s41586-019-1215-2; WO2018 / 226150 & WO2018 / 141749). Geneticevidence from MALT1 -deficient mice suggests that MALT 1 promotes development of Treg cells in vivo, which in turn inhibit several types of immune cells, suppressing the antitumour immune response. Further studies targeting the CBM complex (by either MALT1 inhibition or CARMA1 deletion in Treg cells) led to a gain of effector activity by Treg cells and enhanced control of tumour growth. A MALT1 inhibitor synergized with anti-PD1 therapy in both poorly immunogenic and immunogenic murine melanoma models (doi:10.1038 / s41586-019-1215-2), suggesting a possible combinatorial role of MALT1 inhibitors with immunotherapies, including anti-PD1 , anti-PD-L1 and anti-CTLA4.

[0007] As well as having a use in oncology indications, small-molecule MALT 1 inhibitors may also be effective therapies in inflammatory disorders, for example multiple sclerosis, psoriasis, ulcerative colitis and rheumatoid arthritis. MI-2 has been shown to suppress the differentiation of monocytes into osteoclasts in the presence or absence of TN Fa, and to ameliorate the pathologic bone erosion and synovitis in a mouse collagen-induced arthritis (CIA) model, suggesting a role for MALT 1 inhibitors in the treatment of rheumatoid arthritis (doi:10.1038 / s41598-017-12349-9). The scaffold protein CARD14 forms a signalling complex with BCL10 and MALT1 in keratinocytes and this process is enhanced upon pathogenic CARD14 mutation which as in turn been linked to susceptibility to psoriasis (doi:10.1016 / j.jid.2016.09.031). MALT1 inhibitors have also been successfully tested in mouse models of multiple sclerosis and ulcerative colitis (doi: 10.1186 / 1742-2094-11-124). Pharmacological inhibition of MALT1 protease activity has been shown to suppress endothelial activation through increasing MCPIP1 expression, inhibiting TNFa-induced VCAM-1 expression in HUVECs and LPS-induced VCAM-1 expression in mice, suggesting a possible role for MALT 1 inhibitors in the treatment of vascular inflammatory diseases such as atherosclerosis (doi: 10.1016 / j. cellsig.2018.05.009).

[0008] Homozygous MALT 1 W580S mutations have been determined in patients with combined immunodeficieny (CID). This was associated with low MALT1-W580S protein levels leading to reduced amplitude but extended duration of NF-kB due to impaired negative feedback through reduced HOIL1 cleavage, manifesting clinically in increased dermal and Gl inflammation and increased susceptibility to infection (doi.org / 10.1016 / j.jaci.2013.10.045). Small-molecule ligands known to bind to the MALT1 wild-type allosteric site have been shown to also bind to the W580S mutant leading to enzyme stabilization and reconstitution of protein levels, even after ligand washout. Both scaffolding and protease functions were restored; thus allosteric MALT 1 inhibitors may be able to serve as ‘molecular correctors’ in cases of W80S MALT1 mutations (doi . org / 10.1038 / s41589-018-0222- 1 ) .

[0009] Clinical and pre-clinical studies are ongoing with a variety of MALT1 inhibitors. JNJ-67856633 is a small molecule MALT 1 inhibitor currently in Phi studies in patients with NHL and CLL. A review of MALT1 inhibitor patents has recently been published (doi: 10.1080 / 13543776.2021 .1951703) .

[0010] Therefore, there is an ongoing need for agents capable of MALT 1 inhibition, given the role of MALT1 in multiple indications.SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof as defined herein.

[0012] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0013] In another aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0014] In another aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of diseases or disorders mediated by MALT1.

[0015] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by MALT 1 , said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0016] Examples of diseases or disorders mediated by MALT 1 include: i) lymphomas, leukaemias, carcinomas, and sarcomas; such as non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblasticlarge cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, or GIST (gastrointestinal stromal tumour); and ii) immunological diseases including autoimmune and inflammatory disorders; such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0017] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0018] In another aspect, the present invention provides a method of treating nonHodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukaemia (CLL), or small lymphocytic lymphoma(SLL), said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0019] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0020] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0021] In another aspect, the present invention provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

[0022] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0023] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0024] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, / .e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, / .e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0025] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0026] The phrase “compound of the invention” means those compounds which are disclosed herein.of the Invention

[0027] In a first aspect, the present invention provides a compound selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(methylsulfonamido)cyclopropane-1-carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-2-oxohexahydropyrimidine-5-carboxamide;A / -((1 S)-1-(5-((5-Chloro-4-(difluoromethyl)-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-N-methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;(1 ,3-c / s)- / V-((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1 -carboxamide;A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-2-oxohexahydropyrimidine-5-carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-5-oxomorpholine-2-carboxamide;(1 ,3-c / s)- / V-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1 -carboxamide;(1 ,3-trans)-N1-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-A / 1,A / 3-dimethylcyclobutane-1 ,3-dicarboxamide;(3S)- / V-((1 S)-1-(6-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-A / -methyl-6-oxopiperidine-3-carboxamide;A / -(1-(2-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)-A / - methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;A / -(1-(6-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridazin-3-yl)-2,2,2-trifluoroethyl)-A / - methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;1-(2-Cyanoacetyl)- / V-((1 S)-1-(5-((4,5-dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-A / -methylazetidine-3-carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1-oxide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(oxetane-2-carbonyl)azetidine-3-carboxamide;(3S)-A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)- / V-methyl-5-oxopyrrolidine-3-carboxamide;(3 / ?)-A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-5-oxopyrrolidine-3-carboxamide;A / -(1-(2-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)-A / - methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)-A / -methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1-oxide;A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1-oxide;A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1-oxide;A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)- / V-methyl-5-oxomorpholine-2-carboxamide;(1 ,3-c / s)- / V-(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)- 2, 2, 2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1 -carboxamide;(3S)-A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)- / V-methyl-5-oxopyrrolidine-3-carboxamide;A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;A / -((1 S)-1-(2-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;(1 ,3-frans)- / V-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1-carboxamide;(3S)-A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)- / V-methyl-6-oxopiperidine-3-carboxamide; and(1 ,3-c / s)- / V-((1 S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)- 2, 2, 2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1 -carboxamide.

[0028] Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.

[0029] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0030] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0031] The compounds of this invention typically possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, diastereoisomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesisfrom optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess MALT1 inhibitory activity.

[0032] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D) and3H (T); C may be in any isotopic form including12C,13C, and14C; and O may be in any isotopic form, including16O and18O; and the like.

[0033] It is also to be understood that certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess MALT 1 inhibitory activity.

[0034] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms that possess MALT1 inhibitory activity.

[0035] Compounds of the invention may exist in a number of different tautomeric forms and references to compounds of the invention include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by compounds of the invention. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci- nitro.keto enol enolate

[0036] Compounds of the invention containing an amine function may also form / V- oxides. A reference herein to a compound of the formula I that contains an amine function also includes the / V-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an / V-oxide. Particular examples of / V-oxides are the / V-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. / V-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, / V-oxides can be made by the procedure of L. W.Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0037] The compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.

[0038] Accordingly, the present invention includes those compounds of the invention as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the invention that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the invention may be a synthetically-produced compound or a metabolically-produced compound.

[0039] A suitable pharmaceutically acceptable pro-drug of a compound of the invention is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0040] Various forms of pro-drug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; andh) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0041] The in vivo effects of a compound of the invention may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the invention. As stated hereinbefore, the in vivo effects of a compound of the invention may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0042] It shall also be appreciated that compounds of the invention may also be covalently linked (at any suitable position) to other groups such as, for example, solubilising moieties (for example, PEG polymers), moieties that enable them to be bound to a solid support (such as, for example, biotin-containing moieties), and targeting ligands (such as antibodies or antibody fragments).Pharmaceutical Compositions

[0043] The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Therefore, according to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluent or carrier.

[0044] The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

[0045] The compositions of the invention may be in a form suitable for oral use (for example as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets), for topical use (for example as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels), for transdermal administration such as via transdermal patches, for administration by inhalation (for example as a dry powders, aerosols, suspensions, and solutions), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0046] As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must be of sufficiently high purity to render it pharmaceutically-acceptable.

[0047] Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

[0048] Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The person skilled in the art will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0049] Persons skilled in the art possess the knowledge and skill to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0050] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0051] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0052] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well- known principles of medicine.

[0053] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.Routes of Administration

[0054] The compounds of the invention, or a pharmaceutical composition comprising the a compound of the invention, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e. at the site of desired action).

[0055] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0056] In a preferred embodiment, a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, is administered orally or via injection, such as conveniently by oral administration.

[0057] The compounds of the invention are inhibitors of MALT1. As a consequence, they are potentially useful therapeutic agents for the treatment of diseases or conditions mediated by MALT 1 .

[0058] Thus, in one aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0059] In another aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of diseases or disorders mediated by MALT1.

[0060] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by MALT 1 , said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0061] In another aspect, the present invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of a disease or disorder mediated by MALT 1.

[0062] Examples of particular diseases or conditions that the compounds of formula (I) and their pharmaceutically acceptable salts may be used to treat include, but are not limited to: i) lymphomas, leukaemias, carcinomas, and sarcomas; such as non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin'slymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, or GIST (gastrointestinal stromal tumour); and ii) immunological diseases including autoimmune and inflammatory disorders; such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0063] In particular, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of lymphomas, such as non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0064] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as definedherein, for use in the treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small- cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody- mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0065] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0066] In another aspect, the present invention provides a method of treating non- Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantlecell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0067] In another aspect, the present invention provides a method of treating nonHodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukaemia (CLL), or small lymphocytic lymphoma (SLL), said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0068] In another aspect, the present invention provides a method of inhibiting MALT1 in vitro, said method comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0069] In another aspect, the present invention provides a method of inhibiting MALT1 in vivo, said method comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0070] In another aspect, the present invention provides a method of inhibiting MALT1 in vitro and / or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.Combination Therapies

[0071] The compounds of the invention may be administered alone as a monotherapy or may administered in combination with one or more additional therapeutic agents. The selection of the one or more additional therapeutic agents will of course vary depending on the disease or condition to be treated and its severity.

[0072] It is commonplace to use combination therapies to treat certain medical conditions.

[0073] According to a particular aspect of the invention there is provided a combination suitable for use in the treatment of a disease or condition in which MALT1 is implicated, comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0074] According to this aspect of the invention there is provided a combination suitable for use in the prevention or treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small- cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma,rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody- mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis, the combination comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0075] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0076] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0077] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents in association with a pharmaceutically acceptable diluent or carrier.

[0078] The one or more additional therapeutic agents may comprise a further compound of the present invention. Therefore, in an embodiment, there is provided a pharmaceutical composition which comprises two compounds of the invention, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0079] According to a particular aspect of the invention there is provided a combination suitable for use in the prevention or treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0080] Examples of other therapeutic agents that may be used as part of a combination therapy with a compound of the present invention (e.g. as one of two or more active agents as part of double or triple combinations) include, but are not limited to, the following:(i) BTK (Bruton’s tyrosine kinase) inhibitors such as ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, evobrutinib, fenebrutinib, rilzabrutinib, tolebrutinib, MK1026 (ARQ-531), LOXO-305, elsubrutinib, poseltinib, branebrutinib, spebrutinib, luxeptinib, DTRM-555, JnJ64264681 , BGB-3959, AS-1763 and remibrutinib;(ii) SYK inhibitors such as fostamatinib, entospletinib, HM PL-523, IC-265, SKI-O-703, cerdulatinib, PRT-2761, GSK-264264, SYHX-1901 , MK-8457, HM-43239, R-348 and PUR-1800;(iii) PKC inhibitors such as darovasertib, MS-553, enzastaurin, safingol, ruboxistaurin and AR-13503;(iv) PI3K pathway inhibitors such as alpelisib, duvelisib, copanlisib, idelalisib, umbralisib, serabelisib, CHF-6523, BDP-681 , zandelisib, ART-001 , buparlisib, OP-11 , HMPL-689, dezapelisib, seletalisib, epivotide, IOA-244, SHC-014748M, LX-086, inavolisib, MEN- 1611 , eganelisib, leniolisib, ACP-319, BGB-10188, CYH-33, HS-10352, CMX-2043, ZX- 101A, KA-2237, VS-5584, ASN-003, TQ-B325, AL-58805, gedatolisib, HEC-68498, CLL- 442, tenalisib, dactolisib, GSK-2126458 and bimiralisib;(v) Bel family inhibitors such as ABT-737, HA14-1 , BH3I-1 , A-1155463, A-1331852, A- 1210477, BDA-366, TW-37, S44563, S64315 (MIK665), S63845, BCL-201 , AMG176, AZD-0466, AZD5991 , UMI-77, navitoclax, pelcitoclax, obatoclax, sabutoclax, apogossypol, gossypol, antimycin A, Gambogic acid, LP-118, FCN-338, BGB-11417, UBX-1325, LP-108, VOB-560, lisaftoclax, murizatoclax, venetoclax, ZN-d5 and ABBV- 167;(vi) JAK inhibitors such as gusacitinib, delgocitinib, tofacitinib, abrocitinib, ruxolitinib, baricitinib, fedratinib, upadacitinib, filgotinib, peficitinib, TD-8236, TD-0903, CEE-321 , lorpucitinib, WXSH-0150, SYHX-1901 , cerdulatinib, izencitinib, KL-130008, WP-1066, gusacitinib, INCB-52793, AC-1101 , ATI-1777, SHR-0302, CPL-409116, momelotinib,brepocitinib, TTL-018, TD-5202, LP-0184, INCB-054707, jaktinib, TQ-05105, itacitinib, AZD-0449, GLPG-0555, LW-104, ARQ-252, WXFL-10203614, golidocitinib, deuruxolitinib, CJ-15314, CS-12192, ritlecitinib, R-348, ATI-2138 and ilginatinib;(vii) PIM kinase inhibitors such as uzansertib, TP-3654, MEN-1703, ETH-155008, abemaciclib and SF-1126;(viii) mTORC inhibitors such as rapamycin, sirolimus, novolimus, umirolimus zotarolimus, temsirolimus, everolimus, merilimus, eRapa, ridaforolimus;(ix) Rituximab or other B cell antigen-binding antibodies as well as immune cell redirection agents (e.g. blinatumomab or CAR-T cells);(x) Anti-PD1 antibodies such as nivolumab, pembrolizumab, lambrolizumab, pidilzumab, BGB-A317;(xi) Anti-PD-L1 antibodies such as atezolizemab, avelumab, durvalumab, MEDI-4736 and MPDL3280A;(xii) Antibodies that inhibit the 4-1 BB - ligand interaction such as utomilumab; and(xiii) Antibodies that inhibit the interaction of CTLA-4 and its ligands such as ipilumumab, tremelimumab, or those disclosed in W02014 / 207063.

[0081] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

[0082] Such conjoint / combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0083] Such combination therapies employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges and / or the dosage such as described in the relevant publication reference.EXAMPLESGeneral Procedures:

[0083] Methods for preparing the compounds of this invention are illustrated in the following Examples. Starting materials are made according to procedures known in the art,or as illustrated herein, or are available commercially. Commercial reagents were used without further purification. Where no reaction temperature is included, the reaction was performed at ambient temperature which is typically 17 - 27 °C.

[0084] A person skilled in the art will appreciate that reaction temperatures, reaction times & reagent quantities may be varied from those stated herein.

[0085] Where compounds described in the invention are characterized by1H NMR spectroscopy, spectra were recorded on 400 MHz Bruker Avance III HD instrument and 300 MHz Bruker Fourier HD instrument. Where no temperature is included, the spectra were recorded at ambient temperature. Chemical shift values are expressed in parts per million (ppm). The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, t=triplet, q=quartet, m=multiplet, d=doublet.

[0086] Where compounds described in the invention are characterized by LCMS data, molecular weight is determined using the conditions listed below.Method A: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 50 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method B: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 50 x 2.1 mm. Conditions: 0.05% formic acid in water [eluent A], 0.05% formic acid in MeCN [eluent B],Method C: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 50 x 2.1 mm. Conditions: 0.1% TFA in water [eluent A], 0.1% TFA in MeCN [eluent B],Method D: Shimadzu 2020 (SPD-M40 PDA 220 I 254 nm and MS detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method E: Shimadzu 2020 (SPD-M40 PDA 254 I 280 nm and MS detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method F: Waters Acquity l-Class Plus (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1 % formic acid in water [eluent A], 0.1 % formic acid in MeCN [eluent B],Method G: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: XBridge C18, 130 A, 3.5 pm, 100 x 4.6 mm. Conditions: 5 mMNH4HCO3 in water [eluent A], MeCN [eluent B],Method H: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: XBridge C18, 130 A, 3.5 pm, 150 x 4.6 mm. Conditions: 10 mMNH4HCO3 in water [eluent A], MeCN [eluent B],Method I: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.05% ammonia in water [eluent A], in MeCN [eluent B],Method J: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: YMC-Triart C18, 120 A, 1.9 pm, 50 x 2.1 mm. Conditions: 0.05% formic acid in water [eluent A], MeCN [eluent B],

[0087] Where compounds described in the invention are characterized by GCMS data, molecular weight is determined using the conditions listed below.Method 1 : Shimadzu Nexis GC 2030 with EI-MS detector (GCMS QP2020 NX). Column: HP-5MS III 30 m x 0.32 mm x 0.5 pm. Conditions: Helium carrier gas, Oven temp 35 - 300 °C over 3 min, Injection temp 250 °C, 2 mL / min.

[0088] Preparative HPLC was performed using Shimadzu CBM-20A I SIL-10AP; Shimadzu Nexera; Waters Delta; Gilson GX-271 ; Agilent 1260 Infinity II.

[0089] Preparative SFC was performed using Waters SFC-150-1; Water SFC-150-II; Waters SFC-200; Sepiatec-200.

[0090] Automated purification was carried out using Interchim Puriflash XS 520: Normalphase PF-50SIHP-JP; Reverse-phase PF-15C18HP.Abbreviations:Intermediate SynthesisIntermediate 1 : (S)- / V-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)- / \ / -methylpivalamide

[0091] To a stirred mixture of (S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoro- / V-methylethan- 1-amine (1.0 g, 3.27 mmol, CAS 2771010-86-5) in DCM (10 mL) was added triethylamine (2.68 mL, 18.6 mmol) at 0 °C and stirred for 5 min. Trimethylacetyl chloride (1.37 mL, 11.2 mmol) was added then the mixture was stirred at RT for 16 h. The mixture was poured into water then extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 2-4% EtOAc in petroleum ether) to provide the title compound (1.0 g). LCMS (Method A): 353.2 [M+H]+.Intermediate 2: (S)-A / -(1-(5-((Diphenylmethylene)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methylpivalamide

[0092] To a stirred solution Intermediate 1 (4.3 g, 15.7 mmol) and benzophenone imine (3.94 mL, 23.5 mmol) in toluene (40 mL) was added CS2CO3 (15.3 g, 47.0 mmol) and the mixture was degassed with argon for 5 min. Pd2(dba)s (1.43 g, 1.57 mmol) and X-Phos (1.49 g, 0.74 mmol) were added then the mixture was heated at 110 °C for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (5.0 g). LCMS (Method B): 454.6 [M+H]+.Intermediate 3: (S)- / V-Benzhydryl-6-(2,2,2-trifluoro-1-(methylamino)ethyl)pyridin-3-amine

[0093] To a stirred solution of Intermediate 2 (5.21 g, 11.0 mmol) in THF (50 mL) at -10 °C was added UAIH4 (2M in THF, 11.0 mL, 22.1 mmol) slowly so that the temperature did not exceed 0 °C. The mixture was stirred at -10 °C for 30 min. The mixture was quenched with ice cold aqueous NH4CI and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 15-20% EtOAc in petroleum ether) to provide the title compound (4.0 g). LCMS (Method B): 372.4 [M+H]+.Intermediate 4: tert-Butyl (S)-(1-((1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cvclopropyl)carbamate

[0094] To a stirred solution of Intermediate 3 (0.20 g, 0.54 mmol) and 1-(terf- butoxycarbonylamino)cyclopropanecarboxylic acid (0.16 g, 0.81 mmol, CAS 88950-64-5) in DCM (2.7 mL) was added T3P® (50% MeTHF, 3.3 mL, 5.39 mmol) and triethylamine (1.23 mL, 8.08 mmol) the mixture was stirred at RT for 72 h. The mixture was diluted with water, then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flashchromatography (silica gel, eluting 0-50% EtOAc in cyclohexane) to provide the title compound (0.19 g). LCMS (Method E): 555.5 [M+H]+.Intermediate 5: (S)-1-Amino- / V-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methylcyclopropane-1-carboxamide hydrochloride

[0095] To a stirred solution of Intermediate 4 (0.19 g, 0.33 mmol) in 1 ,4-dioxane (17 mL) was added 4 M HCI in 1 ,4-dioxane (1.0 mL) and stirred at RT for 8 h. The mixture was concentrated under reduced pressure to provide the title compound (0.12 g). LCMS (Method D): 455.2 [M+H]+.Intermediate 6: (S)-A / -(1-(5-(Benzhvdrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / - methyl-1-(methylsulfonamido)cyclopropane-1 -carboxamide

[0096] To a solution of Intermediate 5 (0.51 g, 0.97 mmol) and triethylamine (0.40 mL, 2.90 mmol) in DCM (32 mL) at 0 °C was added methane sulfonyl chloride (90 pL, 1.16 mmol) and stirred at RT for 18 h. The mixture was poured into water and extracted with DCM. The combined organics were washed with 1 M aqueous HCI, saturated aqueous NaHCOs, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0-100% EtOAc in hexane) to provide the title compound (0.36 g). LCMS (Method F): 533.2 [M+H]+.Intermediate 7: (S)-A / -(1-(5-Aminopyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methyl-1- (methylsulfonamido)cyclopropane-l-carboxamide

[0097] To a stirred solution of Intermediate 6 (0.45 g, 0.84 mmol) in MeOH (8.4 mL), was added formic acid (0.32 mL, 8.40 mmol), and palladium on carbon (10%, 27 mg) and the mixture was stirred at 50 °C for 5 h. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCOs and extracted with DCM. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0- 10% MeOH in DCM) to provide the title compound (0.28 g). LCMS (Method F): 367.1 [M+H]+.Intermediate 8: 6-Chloro-7-fluoro-1 / 7-indene

[0098] To a stirred solution of 5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-1-ol (5.00 g, 26.8 mmol, CAS 1597134-92-3) in toluene (0.13 L) at O °C was added pTSA (1.02 g, 5.37 mmol) then the mixture was stirred at 80 °C for 1 h. The mixture was cooled then diluted with water and extracted with TBDME. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting in petroleum ether) to provide the title compound (4.0g).1H NMR (300 MHz; CDCI3) 6: 7.30 (dd, 1 H), 7.11 (d, 1 H), 6.85 - 6.80 (m, 1 H), 6.61 - 6.58 (m, 1 H), 3.48 (t, 2H).Intermediate 9: 5-Chloro-4-fluoro-1 ,3-dihydro-2 / 7-inden-2-one

[0099] Intermediate 8 (2.0 g, 11.6 mmol) was added to a stirred solution of formic acid (7.7 mL) and hydrogen peroxide (35% aqueous, 1.43 mL, 16.3 mmol) at 50 °C then the mixture was stirred at 60 °C for 16 h. Sodium bisulfite (0.48 g) was added and stirred at 55 °C for 1 h. The mixture was concentrated then diluted with water and extracted with DCM. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was mixed with pTSA (0.44 g, 0.20 mmol) in toluene (60 mL) at 90 °C for 2 h. The mixture was diluted with water and extracted into EtOAc. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-20% EtOAc in cyclohexane) to provide the title compound (0.52 g).1H NMR (300 MHz; CDCI3) 6: 7.32 (dt, 1 H), 7.05 (d, 1 H), 3.60 (s, 2H), 3.57 (s, 2H).Intermediate 10: 1 ,3-Dibenzyl-2-oxohexahvdropyrimidine-5-carboxylic acid

[0100] To a solution of ethyl hexahydro-2-oxo-1 ,3-bis(phenylmethyl)-5- pyrimidinecarboxylate (0.65 g, 1.84 mmol, CAS 2301898-53-1) in ethanol (4.0 mL) and water (3.4 mL) was added lithium hydroxide monohydrate (0.15 g, 3.90 mmol) and stirred at RT for 18 h. The mixture was concentrated under reduced pressure, diluted with 1 M aqueous HCI and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.46 g). LCMS (Method E): 325.3 [M+H]+.Intermediate 11 : (S)-A / -(1-(5-(Benzhvdrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1 ,3- dibenzyl- / V-methyl-2-oxohexahvdropyrimidine-5-carboxamide

[0101] Prepared in an analogous manner to Intermediate 4 using Intermediate 3 (0.30 g, 0.86 mmol), Intermediate 10 (0.30 g, 0.93 mmol) and T3P® (50% MeTHF, 2.0 mL, 3.20 mmol) in pyridine (6.2 mL) at RT for 17 h. Purified by trituration in DCM I hexane to provide the title compound (0.36 g). LCMS (Method F): 678.5 [M+H]+.Intermediate 12: (S)-A / -(1-(5-Aminopyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methyl-2- oxohexahvdropyrimidine-5-carboxamide

[0102] Intermediate 11 (0.15 g, 0.22 mmol) was dissolved in TFA (0.4 mL) and trifluoromethane sulfonic acid (0.4 mL) and stirred at RT for 17 h. The mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1% aqueous formicacid with MeCN 10-30% over 10 min, ramped to 95% over 0.2 min and held for 1.8 min) to provide the title compound (43 mg). LCMS (Method I): 332.2 [M+H]+.Intermediate 13: (S)-A / -(1-(5-(Benzhvdrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / - methyltetrahvdro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide

[0103] Prepared in an analogous manner to Intermediate 4 from Intermediate 3 (4.25 g, 10.8 mmol), pyridine (12 mL), T3P® (50% in EtOAc, 32.1 mL, 0.11 mol) and tetrahydro- 2 / 7-thiopyran-4-carboxylic acid 1 ,1-dioxide (5.76 g, 32.3 mmol, CAS 64096-87-3) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 10-50% EtOAc in isohexane) to provide the title compound (4.5 g). LCMS (Method B): 532.6 [M+H]+.Intermediate 14: (S)-A / -(1-(5-Aminopyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methyltetrahydro- 2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide

[0104] To a stirred solution of Intermediate 13 (4.55 g, 2.12 mmol) in MeOH (50 mL), was added palladium on carbon (10%, 2.70 g) and the mixture stirred under a hydrogen atmosphere for 4 h. The mixture was filtered through Celite, washed with EtOAc and concentrated under reduced pressure to provide the title compound (3.0 g). LCMS (Method B): 366.4 [M+H]+.Intermediate 15: 7-Bromo-6-chloro-1 / 7-indene

[0105] Prepared in an analogous manner to Intermediate 8 using 4-bromo-5-chloro-2,3- dihydro-1 / 7-inden-1-ol (1.93 g, 7.81 mmol, CAS 2153981-78-1) and pTSA (0.30 g, 1.56 mmol) in toluene (26 mL) at 80 °C for 1 h, to provide the title compound (1.75 g).1H NMR (300 MHz; CDCh) 6: 7.38 (d, 1 H), 7.26 (d, 1 H), 6.88 (dt, 1 H), 6.62 (dt, 1 H), 3.43 (s, 2H).Intermediate 16: 5-Bromo-4-chloro-1a,6a-dihydro-6 / 7-indenon ,2-b1oxirene

[0106] To a stirred solution of Intermediate 15 (1.00 g, 4.36 mmol) in DCM (30 mL) was added MCPBA (1.61 g, 6.54 mmol) and sodium carbonate (0.54 g, 6.48 mmol) then the mixture was stirred at RT for 16 h. The mixture was filtered, washed with DCM and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting in 0-30% EtOAc in hexane) to provide the title compound (0.49 g).1H NMR (300 MHz; DMSO-d6) 5: 7.60 (d, 1 H), 7.53 - 7.40 (m, 1 H), 4.49 (dd, 1 H), 4.23 (t, 1 H), 3.12 (d, 1 H), 2.98 (dd, 1 H).Intermediate 17: 4-Bromo-5-chloro-1 ,3-dihydro-2 / 7-inden-2-one

[0107] To a stirred solution of Intermediate 16 (0.32 g, 26.8 mmol) in toluene (6.5 mL) was added silica gel (0.31 g) and the mixture was stirred at reflux for 1 h. The mixture was cooled, filtered, washed with toluene and concentrated under reduced pressure to provide the title compound (0.49 g).1H NMR (300 MHz; DMSO-d6) 5: 7.53 (d, 1 H), 7.36 (d, 1 H), 3.68 (s, 2H), 3.57 (s, 2H).Intermediate 18: 4-Bromo-5-chloro-1 ,3-dihvdrospiro[indene-2,2'-n ,31dioxolane1

[0108] To a stirred solution of Intermediate 17 (0.50 g, 1.98 mmol) in 1 ,4-dioxane (6.8 mL) was added 4 M HCI in 1 ,4-dioxane (3.95 mL) and ethylene glycol (2.20 mL, 39.5 mmol) and the mixture was stirred at RT for 18 h. The mixture was quenched with 10% aqueous NaOH then extracted with DCM. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to provide the title compound (0.55 g).1H NMR (400 MHz; DMSO-d6) 5: 7.43 (d, 1 H), 7.24 (d, 1 H), 3.96 (s, 4H), 3.21 (s, 2H), 3.12 (s, 2H).Intermediate 19: 5-Chloro-1 ,3-dihvdrospironndene-2,2'-f1 ,31dioxolane1-4-carbaldehvde

[0109] To a stirred solution of Intermediate 18 (0.50 g, 1.73 mmol) in THF (5.8 mL) at - 78 °C was added butyllithium (1.6 M in hexanes, 1.62 mL) dropwise and the mixture was stirred at -78 °C for 1 h. DMF (0.14 mL, 1.81 mmol) was added and the mixture stirred at -78 °C for 1 h. The mixture was quenched with saturated aqueous NH4CI then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (70 mg). GCMS (Method 1): 238 (M+).Intermediate 20: 5-Chloro-4-(difluoromethyl)-1 ,3-dihydrospironndene-2,2'-n ,31dioxolane1

[0110] To a stirred solution of Intermediate 19 (60 mg, 0.25 mmol) in DCM (1.3 mL) at 0 °C was added DAST (0.10 mL, 0.75 mmol) dropwise and the mixture was stirred at 0 °C for 3 h. The mixture was quenched with saturated aqueous NaHCOs then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (60 mg).1H NMR (300 MHz; DMSO-d6) 5: 7.40 (s, 2H), 7.25 (t, 1 H), 3.96 (s, 4H), 3.27 (s, 2H), 3.09 (s, 2H).Intermediate 21 : 5-Chloro-4-(difluoromethyl)-1 ,3-dihydro-2H-inden-2-one

[0111] A solution of Intermediate 20 (60 mg, 0.23 mmol) in THF (0.6 mL), AcOH (0.2 mL) and water (0.4 mL) was heated at reflux for 16 h. The mixture was quenched with saturated aqueous NaHCOs then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (45 mg).1H NMR (300 MHz; DMSO-d6) 5: 7.53 - 7.48 (m, 2H), 7.28 (t, 1 H), 3.72 (s, 2H), 3.57 (s, 2H).Intermediate 22: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)- / V-methylpivalamide

[0112] To a stirred solution of Intermediate 76 (0.95 g, 3.12 mmol) and 4,5-dichloro-1 ,3- dihydro-2 / 7-inden-2-one (0.99 g, 4.68 mmol, CAS 69392-70-7) in MeOH (24 mL) was added AcOH (0.18 mL, 3.13 mmol) then the mixture was stirred at 60 °C for 6 h. Sodiumcyanoborohydride (0.39 g, 6.24 mmol) was added and stirred at RT for 8 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0 - 15% MeOH in DCM) to provide the title compound (1.0 g). LCMS (Method B): 474.3 [M+H]+.Intermediate 23: A / -(4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)-6-((S)-2,2,2-trifluoro-1- (methylamino)ethyl)pyridin-3-amine

[0113] The title compound (0.85 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 22 (1.1 g, 2.09 mmol) and UAIH4 (2M in THF, 2.09 mL, 4.17 mmol) in THF (10 mL) at 0 °C for 15 min. LCMS (Method B): 390.2 [M+H]+.Intermediate 24: Methyl 2-hvdroxy-3-((4-methoxybenzyl)amino)propanoate

[0114] To a stirred solution of methyl 3-amino-2-hydroxypropanoate hydrochloride (0.50 g, 3.21 mmol, CAS 186393-00-0) in methanol (16 mL) at 0 °C was added triethylamine (1.13 mL, 8.07 mmol) and 4-methoxybenzaldehyde (0.53 g, 3.90 mmol) then the mixture was stirred at 0 °C for 10 min. Sodium borohydride (4.38 g, 116 mmol) was added then the mixture stirred at RT for 16 h. The mixture was quenched with saturated aqueous NH4CI and then extracted with EtOAc. The organic layer was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 20- 100% EtOAc in hexane) to provide the title compound (0.22 g).1H NMR (300 MHz; CDCI3) 5: 7.30 (d, 2H), 6.90 (d, 2H), 4.40 (dd, 1 H), 3.86 (d, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.07 (dd, 2H), 2.93 (dd, 2H).Intermediate 25: Methyl 3-(2-chloro-A / -(4-methoxybenzyl)acetamido)-2- hydroxypropanoate

[0115] To a stirred solution of Intermediate 24 (0.65 g, 2.51 mmol) in DCM (22 mL) at °C was added DIPEA (0.35 mL, 2.01 mmol) and chloroacetyl chloride (0.13 g, 1.19 mmol) and the mixture was stirred at 0 °C for 90 min. The mixture was washed with water. The organic layer was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-60% EtOAc in hexane) to provide the title compound (0.65 g). LCMS (Method D): 315.9 [M+H]+.Intermediate 26: 4-(4-Methoxybenzyl)-5-oxomorpholine-2-carboxylic acid

[0116] To a stirred solution of Intermediate 25 (0.65 g, 2.07 mmol) in THF (20 mL) at °C was added sodium hydride (60% in oil, 0.25 g, 6.25 mmol) and the mixture was stirred at RT for 16 h. The mixture was quenched with 1 M aqueous HCI and stirred for 10 min. The mixture was concentrated under reduced pressure. The crude product was purified byflash chromatography (silica gel, eluting 0-30% MeOH in DCM) to provide the title compound (0.65 g). LCMS (Method D): 263.9 [M-H]’.Intermediate 27: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-

[0117] Prepared in an analogous manner to Intermediate 4 using Intermediate 23 (0.23 g, 0.46 mmol), Intermediate 26 (0.15 g, 0.55 mmol) and T3P® (50% toluene, 2.8 mL, 4.62 mmol) and triethylamine (1.0 mL, 7.18 mmol) in DCM (4.0 mL) at RT for 17 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in hexane) to provide the title compound (0.27 g). LCMS (Method E): 637.0 [M+H]+.Intermediate 28: A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pvridin-2-vl)-2,2,2-trifluoroethvl)-A / -methylpivalamide

[0118] To a stirred solution of Intermediate 1 (0.50 g, 1.39 mmol) and 5-chloro-4- fluoroindan-2-amine hydrochloride (0.37 g, 1.53 mmol, CAS 2740843-37-0) in toluene (10 mL) was added CS2CO3 (1.36 g, 4.16 mmol) and the mixture was degassed with nitrogen for 5 min. RuPhosPdG3 (0.12 g, 0.14 mmol) was added and the mixture was heated at 90 °C for 16 h. The mixture was allowed to cool then diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0- 30% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method B): 458.5 [M+H]+.Intermediate 29: A / -(5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)-6-((S)-2,2,2-trifluoro-1- (methylamino)ethyl)pyridin-3-amine

[0119] The title compound (0.20 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 28 (0.25 g, 0.44 mmol) and LiAIhL (2M in THF, 0.77 mL, 1.54 mmol) in THF (5 mL) at -10 °C for 15 min. LCMS (Method B): 374.4 [M+H]+.Intermediate 30: 1-(6-Bromopyridin-3-yl)-2,2,2-trifluoro-A / -methylethan-1-amine

[0120] A solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (3.0 g, 7.73 mmol, CAS 2565622-62-8) in methylamine in THF (2M, 30 mL) was stirred at 60 °C for 4 h. The mixture was concentrated under reduced pressure and the crude was purified by flash chromatography (silica gel, eluting 10-70% EtOAc in petroleum ether) to provide the title compound (2.5 g). LCMS (Method A): 269.2 [M+H]+.Intermediate 31 : (S)-1-(6-Bromopyridin-3-yl)-2,2,2-trifluoro-A / -methylethan-1-amine

[0121] The title compound (8.5 g) was prepared from Intermediate 30 (28 g) by preparative SFC (LUX Cellulose-i-A3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure100 bar, flow rate: 95 g / min, 90% CO2 with 7% MeOH modifier). LCMS (Method A): 269.0 [M+H]+, 95.7% ee by chiral SFC.Intermediate 32: (S)- / V-(1-(6-Brornopyridin-3-yl)-2,2,2-trifluoroethyl)- / V-methylpivalamide

[0122] To a stirred solution of Intermediate 31 (0.20 g, 0.74 mmol) and triethylamine (0.51 mL, 3.68 mmol) in DCM (4 mL) at 10 °C was added pivaloyl chloride (0.54 mL, 4.42 mmol) and the mixture was stirred at RT for 16 h. The mixture was poured into water and extracted with DCM. The organics were washed with saturated aqueous NaHCOs, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-8% EtOAc in hexane) to provide the title compound (0.20 g). LCMS (Method B): 353.3 [M+H]+.Intermediate 33: A / -((1 S)-1-(6-((4,5-Dichloro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)- / V-methylpivalamide

[0123] To a stirred solution of Intermediate 32 (0.50 g, 1.26 mmol) and 4,5-dichloro-2,3- dihydro-1 / 7-inden-2-amine hydrochloride (0.40 g, 1.26 mmol, CAS 2755418-27-8) in 1 ,4- dioxane (20 mL) was added CS2CO3 (1.23 g, 3.78 mmol) and the mixture was degassed with argon for 5 min. Pd2(dba)s (0.12 g, 0.13 mmol) and Xantphos (0.15 g, 0.25 mmol) were added then the mixture was heated at 100 °C for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (0.35 g). LCMS (Method B): 474.4 [M+H]+.Intermediate 34: A / -(4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)-5-((S)-2,2,2-trifluoro-1- (methylamino)ethyl)pyridin-2-amine

[0124] The title compound (0.14 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 33 (0.36 g, 0.45 mmol) and UAIH4 (2M in THF, 0.45 mL, 0.90 mmol) in THF (10 mL) at 0 °C for 15 min. LCMS (Method B): 390.3 [M+H]+.Intermediate 35: tert-Butyl (5S)-5-(((1 S)-1-(6-((4,5-dichloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-2-oxopiperidine-1- carboxylate

[0125] Prepared in an analogous manner to Intermediate 4 using Intermediate 34 (60 mg, 0.12 mmol), (S)-1-(terf-butoxycarbonyl)-6-oxopiperidine-3-carboxylic acid (88 mg, 0.36 mmol, CAS 1629681-71-5) and T3P® (50% EtOAc, 0.71 mL, 1.12 mmol) in pyridine (0.2 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (60 mg). LCMS (Method B): 615.5 [M+H]+.Intermediate 36: Methyl 2-((5-bromo-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyrimidine-5- carboxylate

[0126] To a stirred solution of methyl 2-chloropyrimidine-5-carboxylate (1.80 g, 10.4 mmol, CAS 287714-35-6) and 5-bromo-2,3-dihydro-1 / 7-inden-2-amine (3.26 g, 14.6 mmol, CAS 73536-88-6) in ethanol (50 mL) was added DIPEA (5.45 mL, 31.3 mmol) and the mixture was heated at 80 °C for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-40% EtOAc in hexane) to provide the title compound (5.0 g). LCMS (Method B): 350.2 [M+H]+.Intermediate 37: 2-((5-Bromo-2,3-dihvdro- inden-2-yl)amino)pyrimidine-5-carboxylicacid

[0127] To a stirred solution of Intermediate 36 (4.0 g, 8.27 mmol) and in MeOH (0.10 L) and water (5 mL) was added potassium hydroxide (1.30 g, 23.2 mmol) and the mixture was heated at 65 °C for 5 h. The mixture was concentrated under reduced pressure. The crude product was acidified with 1 M aqueous HCI and the product filtered to provide the title compound (4.0 g). LCMS (Method B): 336.1 [M+H]+.Intermediate 38: (2-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)methanol

[0128] To a stirred solution of Intermediate 37 (4.0 g, 8.62 mmol) in THF (0.30 L) at -12 °C was added / V-methylmorpholine (0.95 mL, 8.62 mmol) followed by / so-butyl chloroformate (1.12 mL, 8.62 mmol) and stirred at -12 °C for 5 min. Sodium borohydride (0.49 g, 12.9 mmol) in water (10 mL) was added and stirred at RT for 3 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-100% EtOAc in hexane) to provide the title compound (1.2 g). LCMS (Method B): 322.1 [M+H]+.Intermediate 39: 2-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidine-5- carbaldehyde

[0129] To a stirred solution of Intermediate 38 (1.2 g, 2.62 mmol) in DCM (0.15 L) was added manganese dioxide (2.97 g, 34.1 mmol) stirred at RT for 13 h. The mixture was filtered and the filtrate washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.75 g). LCMS (Method B): 320.1 [M+H]+.Intermediate 40: 1-(2-((5-Bromo-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethan-1-ol

[0130] To a stirred solution of Intermediate 39 (0.95 g, 2.63 mmol) in THF (73 mL) at - 20 °C was added TFMTMS (0.56 g, 3.94 mmol) and TBAF (1 M in THF, 3.94 mL) dropwise then stirred at -20 °C for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0- 30% EtOAc in hexane) to provide the title compound (0.47 g). LCMS (Method A): 390.2 [M+H]+.Intermediate 41 : 1-(2-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethan-1-one

[0131] To a stirred solution of Intermediate 40 (0.45 g, 0.87 mmol) in DCM (20 mL) was added manganese dioxide (0.76 g, 8.69 mmol) stirred at RT for 7 h. The mixture was filtered and the filtrate washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.40 g). LCMS (Method B): 388.2 [M+H]+.Intermediate 42: A / -(5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)-5-(2,2,2-trifluoro-1- (methylimino)ethyl)pyrimidin-2-amine

[0132] To a stirred solution of Intermediate 41 (0.25 g, 0.32 mmol) and titanium isopropoxide (0.20 mL, 0.65 mmol) in toluene (20 mL) was added methylamine (2 M in THF, 2.43 mL) and stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.25 g). LCMS (Method B): 401.1 [M+H]+.Intermediate 43: A / -(5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)-5-(2,2,2-trifluoro-1- (methylamino)ethyl)pyrimidin-2-amine

[0133] To a stirred solution of Intermediate 42 (0.25 g, 0.49 mmol) in MeOH (6 mL) at 0 °C was added sodium cyanoborohydride (61 mg, 0.98 mmol) then stirred at RT for 2 h. The mixture was concentrated under reduced pressure then diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 85% CO2 with 15% MeOH modifier) to provide the title compound (0.11 g). LCMS (Method G): 403.2 [M+H]+.Intermediate 44: Ethyl 6-((5-bromo-2,3-dihydro-1 / 7-inden-2-

[0134] Prepared in an analogous manner to Intermediate 36 using methyl 6- bromopyridazine-3-carboxylate (1.80 g, 8.29 mmol, CAS 65202-52-0), 5-bromo-2,3- dihydro-1 / 7-inden-2-amine (1.80 g, 6.64 mmol, CAS 73536-88-6), DI PEA (4.33 mL, 24.9mmol) in ethanol (36 mL) at 80 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-45% EtOAc in petroleum ether) to provide the title compound (1.1 g). LCMS (Method B): 364.3 [M+H]+.Intermediate 45: (6-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridazin-3-yl)methanol

[0135] To a stirred solution of Intermediate 44 (1.0 g, 2.57 mmol) in THF (15 mL) at -20 °C was added UAIH4 (2 M in THF, 1.93 mL) then stirred at -20 °C for 1 h. The mixture was quenched with saturated aqueous NH4CI and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC (silica gel, eluting 0-100% EtOAc in petroleum ether the 0-10% MeOH in DOM) to provide the title compound (0.72 g). LCMS (Method B): 322.2 [M+H]+.Intermediate 46: 6-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridazine-3- carbaldehyde

[0136] To a stirred solution of Intermediate 45 (0.70 g, 2.10 mmol) in DCM (15 mL) was added manganese dioxide (2.74 g, 31.5 mmol) stirred at RT for 5 h. The mixture was filtered and the filtrate concentrated under reduced pressure to provide the title compound (0.53 g). LCMS (Method B): 320.2 [M+H]+.Intermediate 47: 1-(6-((5-Bromo-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridazin-3-yl)-2,2,2- trifluoroethan-1-ol

[0137] Prepared in an analogous manner to Intermediate 40 using Intermediate 46 (0.47 g, 1.18 mmol), TFMTMS (0.25 g, 1.77 mmol) and TBAF (1 M in THF, 1.77 mL) in THF (38 mL) at -20 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-50% EtOAc in hexane) to provide the title compound (0.15 g). LCMS (Method B): 390.3 [M+H]+.Intermediate 48: 1-(6-((5-Bromo-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridazin-3-yl)-2,2,2- trifluoroethan-1-one

[0138] To a stirred solution of Intermediate 47 (0.15 g, 0.34 mmol) in DCM (18 mL) was added manganese dioxide (0.44 g, 5.10 mmol) stirred at RT for 7 h. The mixture was filtered and the filtrate was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.14 g). LCMS (Method B): 388.2 [M+H]+.Intermediate 49: A / -(5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)-6-(2,2,2-trifluoro-1- (methylimino)ethyl)pyridazin-3-amine

[0139] To a stirred solution of Intermediate 48 (0.14 g, 0.33 mmol) and titanium isopropoxide (0.20 mL, 0.67 mmol) in toluene (7.4 mL) was added methylamine (2 M inTHF, 2.50 mL) and stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.15 g). LCMS (Method B): 401.1 [M+H]+.Intermediate 50: / V-(5-Bromo-2,3-dihvdro-1 / 7-inden-2-yl)-6-(2,2,2-trifluoro-1- (methylamino)ethyl)pyridazin-3-amine

[0140] Prepared in an analogous manner to Intermediate 43 using Intermediate 49 (0.90 g, 1.06 mmol), sodium cyanoborohydride (0.13 g, 2.12 mmol) in MeOH (15 mL) at 0 °C then stirred at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0 - 40% EtOAc in hexane) to provide the title compound (0.11 g). LCMS (Method B): 403.3 [M+H]+.Intermediate 51 : tert-Butyl 3-(((1 S)-1-(5-((4,5-dichloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2, 2, 2-trifluoroethyl)(methyl)carbamoyl)azetidine-1 -carboxylate

[0141] Prepared in an analogous manner to Intermediate 4 using Intermediate 23 (0.30 g, 0.71 mmol), 1-terf-butoxycarbonylazetidine-3-carboxylic acid (0.18 g, 0.85 mmol, CAS 142253-55-2) and T3P® (50% toluene, 2.94 mL, 4.99 mmol) and triethylamine (2.94 mL, 21.1 mmol) in DCM (1.5 mL) at RT for 1 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in hexane) to provide the title compound (0.39 g). LCMS (Method B): 573.6 [M+H]+.Intermediate 52: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-A / -methylazetidine-3-carboxamide TFA salt

[0142] To a stirred solution of Intermediate 51 (0.39 g, 0.33 mmol) in DCM (8 mL) was added TFA (3.6 mL) and stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (0.32 g). LCMS (Method A): 473.3 [M+H]+.Intermediate 53: Methyl tetrahydro-2 / 7-thiopyran-4-carboxylate 1 -oxide

[0143] To a stirred solution of methyl tetrahydrothiopyran-4-carboxylate (3.50 g, 19.2 mmol, CAS 128094-82-6) in MeOH (0.22 L) at 0 °C was added sodium periodate (4.52 g, 21.1 mmol) in water (54 mL) then stirred at RT for 20 h. The mixture was concentrated under reduced pressure then diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (2.0 g). LCMS (Method B): 177.3 [M+H]+.Intermediate 54: Methyl 1-(((benzyloxy)carbonyl)imino)hexahvdro-1A6-thiopyran-4- carboxylate 1 -oxide

[0144] To a stirred solution of Intermediate 53 (2.0 g, 10.1 mmol) in DCM (25 mL) at was added iodobenzene diacetate (4.88 g, 15.2 mmol), magnesium oxide (1.63 g, 40.4 mmol), rhodium diacetate (0.22 g, 0.51 mmol) and benzyl carbamate (2.11 g, 15.2 mmol, CAS 621-84-1) then stirred at RT for 16 h. The mixture was diluted with water andextracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (1.8 g). LCMS (Method B): 326.4 [M+H]+.Intermediate 55: 1-(((Benzyloxy)carbonyl)imino)hexahvdro-1A6-thiopyran-4-carboxylic acid 1 -oxide

[0145] To a stirred solution of Intermediate 54 (0.48 g, 1.25 mmol) in THF (42 mL) at was added lithium hydroxide (0.12 g, 4.98 mmol) in water (5.2 mL) and MeOH (5.2 mL) then stirred at RT for 16 h. The mixture was diluted with 10% aqueous citric acid and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure, to provide the title compound (0.40 g). LCMS (Method B): 312.4 [M+H]+.Intermediate 56: Benzyl (4-(((1 S)-1-(5-((4,5-dichloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-1-oxidotetrahydro-2 / 7-1A6- thiopyran-1-ylidene)carbamate

[0146] Prepared in an analogous manner to Intermediate 4 using Intermediate 23 (0.30 g, 0.71 mmol), Intermediate 55 (0.48 g, 1.40 mmol) and T3P® (50% EtOAc, 2.22 g, 7.0 mmol) and triethylamine (0.29 mL, 2.10 mmol) in DCM (2.9 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in isohexane) to provide the title compound (0.25 g). LCMS (Method B): 683.5 [M+H]+.Intermediate 57: A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-A / -methylpivalamide

[0147] To a stirred solution of Intermediate 32 (0.30 g, 0.81 mmol) in toluene (6 mL) was added 5-chloro-4-fluoro-indan-2-amine hydrochloride (0.25 g, 1.13 mmol, CAS 2740843-37-0), and CS2CO3 (0.79 g, 2.42 mmol) and the mixture was degassed with argon for 10 min. Pd-PEPPSI-iHeptCI (55 mg, 0.08 mmol) was added then the mixture was heated at 100 °C for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-100% EtOAc in hexane) to provide the title compound (0.11 g). LCMS (Method B): 458.4 [M+H]+.Intermediate 58: A / -(5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)-5-((S)-2,2,2-trifluoro-1- (methylamino)ethyl)pyridin-2-amine

[0148] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 57 (0.16 g, 0.31 mmol) and UAIH4 (2M in THF, 0.92 mL, 1.84 mmol) in THF (5 mL) at 0 °C for 30 min. LCMS (Method B): 374.2 [M+H]+.Intermediate 59: 2-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidine-5- carbaldehyde

[0149] To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (0.88 g, 6.17 mmol, CAS 933702-55-7) in ethanol (30 mL) was added 5-chloro-indan-2-amine hydrochloride (1.25 g, 5.94 mmol, CAS 73536-86-4), and DI PEA (5.38 mL, 30.9 mmol) and the mixture was heated at 85 °C for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-50% EtOAc in hexane) to provide the title compound (0.45 g). LCMS (Method B): 274.2 [M+H]+.Intermediate 60: 1-(2-((5-Chloro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethan-1-ol

[0150] Prepared in an analogous manner to Intermediate 40 using Intermediate 59 (0.60 g, 1.91 mmol), TFMTMS (0.41 g, 2.86 mmol) and TBAF (1 M in THF, 2.86 mL) in THF (40 mL) at -20 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.28 g).1H NMR (400 MHz; CDCI3) 6: 8.38 (s, 2H), 7.21 (s, 1 H), 7.15 (s, 2H), 5.47 (d, 1 H), 4.97 - 4.78 (m, 2H), 3.42 - 3.32 (m, 2H), 2.93 - 2.80 (m, 2H) - OH not observed.Intermediate 61 : 1-(2-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethan-1-one

[0151] To a stirred solution of Intermediate 60 (0.75 g, 2.18 mmol) in DCM (15 mL) was added manganese dioxide (2.85 g, 32.7 mmol) stirred at RT for 16 h. The mixture was filtered and the filtrate washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.63 g). LCMS (Method B): 342.2 [M+H]+.Intermediate 62: A / -(5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)-5-(2,2,2-trifluoro-1- (methylimino)ethyl)pyrimidin-2-amine

[0152] To a stirred solution of Intermediate 61 (0.63 g, 1.84 mmol) and titanium isopropoxide (0.48 mL, 1.59 mmol) in toluene (20 mL) was added methylamine (2 M in THF, 5.95 mL) and stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.63 g). LCMS (Method G): 355.2 [M+H]+.Intermediate 63: A / -(5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)-5-(2,2,2-trifluoro-1- (methylamino)ethyl)pyrimidin-2-amine

[0153] Prepared in an analogous manner to Intermediate 43 using Intermediate 62 (0.63 g, 1.47 mmol), sodium cyanoborohydride (0.19 g, 2.95 mmol) in MeOH (20 mL) at 0 °C then stirred at RT for 2 h. Purified by flash chromatography (silica gel, eluting 12-15% EtOAc in hexane) to provide the title compound (0.31 g). LCMS (Method B): 357.2 [M+H]+.Intermediate 64: 2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-

[0154] To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (1.35 g, 9.46 mmol, CAS 933702-55-7) in ethanol (30 mL) was added 4-fluoro-5-chloro-indan-2-amine hydrochloride (1.50 g, 6.75 mmol, CAS 2740843-37-0), and DIPEA (5.88 mL, 33.8 mmol) and the mixture was heated at 80 °C for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0- 20% EtOAc in petroleum ether) to provide the title compound (0.75 g). LCMS (Method B): 292.2 [M+H]+.Intermediate 65: 1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5- yl)-2,2,2-trifluoroethan-1-ol

[0155] Prepared in an analogous manner to Intermediate 40 using Intermediate 64 (1.10 g, 3.17 mmol), TFMTMS (0.68 g, 4.75 mmol) and TBAF (1 M in THF, 4.75 mL) in THF (20 mL) at-10 °C then RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method B): 362.3 [M+H]+.Intermediate 66: 1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5- yl)-2,2,2-trifluoroethan-1-one

[0156] To a stirred solution of Intermediate 65 (0.70 g, 1.72 mmol) in DCM (10 mL) and THF (10 mL) was added manganese dioxide (2.25 g, 25.8 mmol) stirred at RT for 16 h. The mixture was filtered and the filtrate washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.62 g). LCMS (Method B): 360.3 [M+H]+.Intermediate 67: / V-(5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)-5-(2,2,2-trifluoro-1- (methylimino)ethyl)pyrimidin-2-amine

[0157] To a stirred solution of Intermediate 66 (0.62 g, 1.72 mmol) and titanium isopropoxide (1.01 mL, 3.45 mmol) in toluene (20 mL) was added methylamine (2 M in THF, 12.9 mL) and stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.64 g). LCMS (Method G): 373.2 [M+H]+.Intermediate 68: A / -(5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)-5-(2,2,2-trifluoro-1- i-2-amine

[0158] Prepared in an analogous manner to Intermediate 43 using Intermediate 67 (0.64 g, 1.72 mmol), sodium cyanoborohydride (0.30 g, 4.72 mmol) in MeOH (10 mL) at 0 °C then stirred at RT for 4 h. Purified by flash chromatography (silica gel, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (0.40 g). LCMS (Method B): 375.3 [M+H]+.Intermediate 69:-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / - / -indent- idin-2-yl)-2,2,2-tri•-2 / 7-1A6--yli

[0159] Prepared in an analogous manner to Intermediate 4 using Intermediate 29 (0.77 g, 1.73 mmol), Intermediate 55 (1.09 g, 3.46 mmol) and T3P® (50% EtOAc, 5.50 g, 17.3 mmol) and triethylamine (5.19 mL, 5.19 mmol) in DCM (7.4 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in isohexane) to provide the title compound (0.70 g). LCMS (Method B): 668.1 [M+H]+. intermediate 70:i-chloro-4-fluoro-2,3-di»-1 / 7-inden-2-•-2 / 7-1A6-

[0160] Prepared in an analogous manner to Intermediate 4 using Intermediate 58 (0.32 g, 0.70 mmol), Intermediate 55 (0.72 g, 2.1 1 mmol) and T3P® (50% EtOAc, 4.18 mL, 7.02 mmol) in pyridine (3.2 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-15% MeOH in DCM) to provide the title compound (0.34 g). LCMS (Method B): 667.6 [M+H]+.-1-,i-ch loro-4-f I uoro-2 , 3-d ii-1 / 7-inden-2-triI-2 / 7-1A6-i-ch loro-4-f I uoro-2 , 3-d ii-1 / 7-inden-2-I-2 / 7-1A6-

[0161] Prepared in an analogous manner to Intermediate 4 using Intermediate 68 (0.32 g, 0.75 mmol), Intermediate 55 (0.35 g, 1.13 mmol) and T3P® (50% EtOAc, 5.63 mL, 19.4 mmol) in pyridine (0.9 mL) at 60 °C for 5 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether) and by preparative SFC (PrincetonSFC 2- Ethylpyridine, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 88% CO2 with 12% 1 : 1 MeCN I IPA modifier) to provide Intermediate 71 a (0.19 g) as peak 1 and Intermediate 71 b (0.21 g) as peak 2. Intermediate 71 a: LCMS (Method J): 668.7 [M+H]+; Intermediate 71 b: LCMS (Method J): 668.7 [M+H]+.Intermediate 72: 4-acid

[0162] To a stirred solution of 4-terf-butoxycarbonylmorpholine-2-carboxylic acid (5.04 g, 21.8 mmol, CAS 189321-66-2) in EtOAc (0.15 L) at 0 °C was added sodium periodate (18.7 g, 87.2 mmol) in water (0.15 L) and ruthenium (III) chloride (0.34 g, 1.09 mmol) then stirred at RT for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-50% EtOAc in hexane) to provide the title compound (2.8 g). LCMS (Method B): 244.3 [M-H]’.Intermediate 73: terf-Butyl 2-(((1 S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- idin-3-yl)-2,2,2-tri i-5-oxomorpholine-4-

[0163] Prepared in an analogous manner to Intermediate 4 using Intermediate 72 (0.26 g, 0.99 mmol), Intermediate 58 (0.14 g, 0.33 mmol) and T3P® (50% EtOAc, 1.96 mL, 3.30 mmol) and triethylamine (46 pL, 0.33 mmol) in DCM (0.2 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-15% MeOH in DCM) to provide the title compound (0.11 g). LCMS (Method B): 601.6 [M+H]+.Intermediate 74: Methyl (1 ,3-trans)-3-(methylcarbamoyl)cyclobutane-1-carboxylate

[0164] To a stirred solution of methyl trans-3-(methylcarbamoyl)cyclobutane-1- carboxylate (100 mg, 0.63 mmol, CAS 1401103-71-6) in DCM (3.2 mL) at 0 °C was added oxalyl chloride (64 pL, 0.76 mmol) then the mixture was stirred at RT for 2 h. Methylamine (1M in THF, 3.16 mL, 3.16 mmol) was added then the mixture stirred at RT for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.20 g).1H NMR (300 MHz; DMSO-d6) 5: 7.73 (br s, 1 H), 3.61 (s, 3H), 3.15 - 2.93 (m, 2H), 2.56 (d, 3H), 2.33 - 2.16 (m, 4H).Intermediate 75: (1 ,3-trans)-3-(Methylcarbamoyl)cyclobutane-1-carboxylic acid

[0165] To a stirred solution of Intermediate 74 (0.20 g, 1.17 mmol) in THF (2.2 mL) and MeOH (1.1 mL) was added lithium hydroxide (56 mg, 2.34 mmol) and the mixture was stirred at RT for 3 h. The mixture was concentrated under reduced pressure and dissolved in MeOH and treated with Amberlite® (IR 120 H form) and filtered to provide the title compound (0.19 g).1H NMR (300 MHz; DMSO-d6) 5: 7.65 (br d, 1 H), 2.99 - 2.80 (m, 2H), 2.55 (dd, 3H), 2.30 - 2.14 (m, 4H) - OH not observed.Intermediate 76: (S)- / V-(1-(5-Aminopyridin-2-yl)-2,2,2-

[0166] To a stirred solution of Intermediate 2 (2.96 g, 4.70 mmol) in THF (32 mL) was added 4 M HCI in 1 ,4-dioxane (21 .7 mL) and stirred at RT for 4 h. The mixture was pouredinto saturated aqueous NaHCOs and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to provide the title compound (1.40 g). LCMS (Method B): 290.3 [M+H]+.Intermediate 77: tert-Butyl (5S)-5-((1-(2-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-2-oxopiperidine-1- carboxylate

[0167] Prepared in an analogous manner to Intermediate 4 using Intermediate 68 (0.28 g, 0.67 mmol), (S)-1-(terf-butoxycarbonyl)-6-oxopiperidine-3-carboxylic acid (0.25 g, 1.01 mmol, CAS 1629681-71-5) and T3P® (50% in EtOAc, 1.98 mL, 6.72 mmol) with triethylamine (0.28 mL, 2.02 mmol) in DCM (4.5 mL) at RT for 5 h. Purified by flash chromatography (silica gel, 0-70% EtOAc in petroleum ether) to provide the title compound (0.13 g). LCMS (Method B): 600.4 [M+H]+.Synthesis of ExamplesExample 1 : A / -((1S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methyl-1- (methylsulfonamido)cyclopropane-l -carboxamide

[0168] To a stirred solution of 5-Chloro-4-fluoro-1 ,3-dihydro-2 / 7-inden-2-one (Intermediate 9; 0.21 g, 1.15 mmol) and (S)- / V-(1-(5-Aminopyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(methylsulfonamido)cyclopropane-1-carboxamide(Intermediate 7; 0.28 g, 0.76 mmol) in MeOH (3.8 mL) was added AcOH (48 pL, 0.84 mmol) then the mixture was stirred at 60 °C for 6 h. Sodium cyanoborohydride (0.19 g, 3.06 mmol) was added and the mixture stirred at RT for 18 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Kinetex XB-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.1 % aqueous formic acid with MeCN 40-60% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) gave the title compound (7.8 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.12 - 7.97 (m, 2H), 7.37 (t, 1 H), 7.10 (d, 2H), 7.05 - 6.98 (m, 1 H), 6.52 (d, 1 H), 6.20 (q, 1 H), 4.42 - 4.32 (m,1 H), 3.47 - 3.36 (m, 3H), 3.10 (br s, 2H), 2.87 (s, 3H), 2.85 - 2.81 (m, 2H), 1.28 - 1.06 (m, 4H). LCMS (Method A): 535.4 [M+H]+.Example 2: A / -((1S)-1-(5-((4,5-Dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-A / -methyl-2-oxohexahydropyrimidine-5-carboxamide

[0169] Prepared in an analogous manner to Example 1 using 4,5-dichloro-1 ,3-dihydro- 2 / 7-inden-2-one (62 mg, 0.26 mmol, CAS 69392-70-7), Intermediate 12 (43 mg, 0.13 mmol), AcOH (10 pL, 0.17 mmol) in MeOH (0.9 mL) at RT for 3 h, then sodium cyanoborohydride (50 mg, 0.80 mmol) at RT for 17 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.05% aqueous ammonia with MeCN 40-50% over 6 min, held for 10 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 53% CO2 with 47% (10% NH4HCO3 in 1 :1 MeCN I MeOH modifier) to provide the title compound (6.1 mg) as Peak 1.1H NMR (400 MHz; DMSO-d6) 5: 8.02 (d, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 7.14 (d, 1 H), 7.02 (dd, 1 H), 6.58 - 6.54 (m, 1 H), 6.36 (q, 1 H), 6.25 - 6.20 (m, 2H), 4.38 - 4.31 (m, 1 H), 3.46 - 3.36 (m, 2H), 3.30 - 3.12 (m, 5H), 3.05 (s, 3H), 2.93 - 2.82 (m, 2H). LCMS (Method A): 516.3 [M+H]+.Example 3: A / -((1 S)-1-(5-((5-Chloro-4-(difluoromethyl)-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methyltetrahvdro-2H-thiopyran-4- carboxamide 1 ,1 -dioxide

[0170] Prepared in an analogous manner to Example 1 using Intermediate 21 (45 mg, 0.21 mmol), Intermediate 14 (0.11 g, 0.31 mmol), AcOH (6 pL, 0.10 mmol) in MeOH (1.0 mL) at 50 °C for 16 h, then sodium cyanoborohydride (78 mg, 1.25 mmol) at RT for 72 h. Purified by Prep-TLC (5% MeOH in DCM). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) to provide the title compound (6.2 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.06 - 8.01 (m, 1 H), 7.46 - 7.12 (m, 4H), 7.10 - 7.01 (m, 1 H), 6.58 - 6.48 (m, 1 H), 6.38 (q, 1 H), 4.38 - 4.30 (m, 1 H), 3.52 (dd, 1 H), 3.40 - 3.36(m, 1 H), 3.30 - 3.05 (m, 6H), 3.02 (s, 3H), 2.81 (dd, 1 H), 2.20 - 1.95 (m, 4H). LCMS (Method A): 566.4 [M+H]+.Example 4: (1,3-c / s)-A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methyl-3-(methylsulfonyl)cyclobutane- 1 -carboxamide

[0171] To a stirred solution of A / -(4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)-6-((S)-2,2,2- trifluoro-1-(methylamino)ethyl)pyridin-3-amine (Intermediate 23; 65 mg, 0.15 mmol), and (1 ,3-c / s)-3-methanesulfonylcyclobutane-1-carboxylic acid (35 mg, 0.20 mmol, CAS 1773508-26-1) in pyridine (1.5 mL) was added T3P® (50% toluene, 0.27 mL, 0.45 mmol) and the mixture stirred at RT for 16 h. The mixture was diluted with water, then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.1 % aqueous formic acid with MeCN 60% isocratic over 11 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) to provide the title compound (14 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 6: 8.02 (d, 1 H), 7.43 (dd, 1 H), 7.24 (dd, 1 H), 7.16 (d, 1 H), 7.05 (dd, 1 H), 6.58 (br s, 1 H), 6.33 (q, 1 H), 4.38 - 4.32 (m, 1 H), 4.00 - 3.88 (m, 1 H), 3.35 - 3.30 (m, 3H), 2.92 - 2.85 (m, 8H), 2.47 - 2.35 (m, 4H). LCMS (Method H): 550.3 [M+H]+.Example 5: A / -((1S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methyl-2-oxohexahydropyrimidine-5- carboxamide

[0172] Prepared in an analogous manner to Example 1 using Intermediate 9 (35 mg, 0.18 mmol), Intermediate 12 (30 mg, 0.09 mmol), AcOH (7 pL, 0.12 mmol) in MeOH (0.6 mL) at RT for 17 h, then sodium cyanoborohydride (35 mg, 0.56 mmol) at RT for 2 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.05%aqueous ammonia with MeCN 40-60% over 10 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 53% CO2 with 47% (10% NH4HCO3 in 1 :1 MeCN I MeOH modifier) to provide the title compound (7.2 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.02 (d, 1 H), 7.37 (t, 1 H), 7.14 (dd, 2H), 7.02 (dd, 1 H), 6.54 (d, 1 H), 6.36 (q, 1 H), 6.25 - 6.20 (m, 2H), 4.39 - 4.32 (m, 1 H), 3.46 - 3.36 (m, 2H), 3.30 - 3.12 (m, 5H), 3.05 (s, 3H), 2.93 - 2.82 (m, 2H). LCMS (Method A): 500.3 [M+H]+.Example 6: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)- / V-methyl-5-oxomorpholine-2-carboxamide

[0173] A solution of A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)- pyridin-2-yl)-2,2,2-trifluoroethyl)-4-(4-methoxybenzyl)-A / -methyl-5-oxomorpholine-2- carboxamide (Intermediate 27; 0.23 g, 0.34 mmol) in TFA (9 mL) was stirred at 80 °C for 5 days. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCOs and extracted with DCM. The combined organics were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.05% aqueous ammonia with MeCN 45-65% over 10 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide the title compound (5.1 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.09 (d, 1 H), 8.02 (d, 1 H), 7.44 (d, 1 H), 7.25 (d, 1 H), 7.15 (d, 1 H), 7.03 (dd, 1 H), 6.57 (d, 1 H), 6.29 (q, 1 H), 4.77 (dd, 1 H), 4.38 - 4.30 (m, 1 H), 4.08 (dd, 2H), 3.55 - 3.35 (m, 4H), 3.03 (s, 3H), 2.92 - 2.83 (m, 2H). LCMS (Method A): 517.2 [M+H]+.Example 7: (1,3-c / s)-A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane- 1 -carboxamide

[0174] Prepared in an analogous manner to Example 4 using Intermediate 29 (0.10 g, 0.24 mmol), (1 ,3-c / s)-3-methanesulfonylcyclobutane-1-carboxylic acid (46 mg, 0.26 mmol, CAS 1773508-26-1) and T3P® (0.23 g, 0.71 mmol) in pyridine (1.2 mL) at RT for 16 h. Purified by preparative HPLC (Kinetex XB-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.1% aqueous formic acid with MeCN 50-70% over 11 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (Chiralpak®-IC, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% (0.5% diethylamine in MeOH) modifier) to provide the title compound (14 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.37 (t, 1 H), 7.13 (dd, 2H), 7.02 (dd, 1 H), 6.53 (d, 1 H), 6.33 (q, 1 H), 4.40 - 4.32 (m, 1 H), 3.98 - 3.85 (m, 1 H), 3.50 - 3.30 (m, 3H), 2.90 - 2.82 (m, 8H), 2.47 - 2.36 (m, 4H). LCMS (Method A): 534.3 [M+H]+.Example 8: (1,3-trans)-A / 1-((1S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / 1,A / 3-dimethylcyclobutane-1,3- dicarboxamide

[0175] Prepared in an analogous manner to Example 4 using Intermediate 29 (0.12 g, 0.31 mmol), Intermediate 75 (0.13 g, 0.61 mmol), T3P® (50% in THF, 2.0 mL, 3.30 mmol) and triethylamine (0.64 mL, 4.59 mmol) in DCM (3.1 mL) at RT for 48 h. Purified by preparative HPLC (Kinetex XB-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.1% aqueous formic acid with MeCN 51% isocratic over 11 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 57% CO2 with 43% MeOH modifier) to provide the title compound (6.5 mg) as Peak 1.1H NMR (400 MHz; DMSO-de) 5: 8.01 (d, 1 H), 7.69 (br d, 1 H), 7.37 (t, 1 H), 7.13 (dd, 2H), 7.02 (dd, 1 H), 6.53 (d, 1 H), 6.39 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.45 - 3.32 (m, 3H), 2.90 - 2.80 (m, 6H), 2.57 (d, 3H), 2.47 - 2.36 (m, 4H). LCMS (Method H): 513.4 [M+H]+.Example 9: (3S)-A / -((1S)-1-(6-((4,5-Dichloro-2,3-dihvdro-1H-inden-2- yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)- / V-methyl-6-oxopiperidine-3-carboxamide

[0176] A solution of tert-Butyl (5S)-5-(((1 S)-1-(6-((4,5-dichloro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-2-oxopiperidine-1- carboxylate (Intermediate 35; 60 mg, 76 pmol) in DCM (2.0 mL) and TFA (12 pL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCCh and extracted with DCM. The combined organics were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% MeOH modifier). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide the title compound (5.6 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 6: 8.00 (br s, 1 H), 7.49 - 7.37 (m, 3H),7.28 - 7.21 (m, 2H), 6.54 (d, 1 H), 6.37 (q, 1 H), 4.69 - 4.62 (m, 1 H), 3.41 - 3.35 (m, 2H),3.28 - 3.12 (m, 3H), 2.95 (s, 3H), 2.94 - 2.86 (m, 2H), 2.23 - 2.18 (m, 2H), 1.88 - 1 .71 (m, 2H). LCMS (Method C): 515.3 [M+H]+.Example 10: A / -(1-(2-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)- 2,2,2-trifluoroethyl)-A / -methyltetrahydro-2H-thiopyran-4-carboxamide 1,1 -dioxide

[0177] Prepared in an analogous manner to Example 4 using Intermediate 43 (80 mg, 0.20 mmol), tetrahydro-2 / 7-thiopyran-4-carboxylic acid 1 ,1-dioxide (70 mg, 0.40 mmol, CAS 64096-87-3) and T3P® (50% in EtOAc, 0.63 g, 1.97 mmol) in pyridine (0.6 mL) at 50 °C for 5 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane). Chiral purification by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% (0.2% ammonia in 1 :1 MeCN I MeOH) modifier) to provide the title compound (4.1 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 6: 8.34 (br s, 2H), 7.91 (d, 1 H), 7.42 (s, 1 H), 7.32 (d, 1 H), 7.17 (d, 1 H), 6.40 (q, 1 H), 4.66 - 4.58 (m, 1 H), 3.33 - 3.05 (m, 7H), 2.98 (s, 3H), 2.95 - 2.82 (m, 2H), 2.12 - 1.94 (m, 4H). LCMS (Method A): 561.3 [M+H]+.Example 11 : A / -(1-(6-((5-Bromo-2,3-dihvdro-1H-inden-2-yl)amino)pyridazin-3-yl)-2,2,2-trifluoroethyl)-A / -methyltetrahvdro-2H-thiopyran-4-carboxamide 1,1 -dioxide

[0178] Prepared in an analogous manner to Example 4 using Intermediate 50 (0.10 g, 0.24 mmol), tetrahydro-2 / 7-thiopyran-4-carboxylic acid 1 ,1-dioxide (87 mg, 0.49 mmol, CAS 64096-87-3) and T3P® (50% in EtOAc, 0.77 g, 2.44 mmol) in pyridine (20 mL) at 60 °C for 4 h. Purified by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% MeOH modifier). Chiral purification by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2with 50% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide the title compound (4.0 mg) as Peak 1.1H NMR (400 MHz; DMSO-d6) 5: 7.49 (br s, 1 H), 7.42 (d, 1 H), 7.37 - 7.33 (m, 1 H), 7.24 - 7.18 (m, 2H), 6.85 (d, 1 H), 6.53 (q, 1 H), 4.77 - 4.68 (m, 1 H), 3.33 - 3.05 (m, 7H), 3.01 (s, 3H), 2.93 - 2.79 (m, 2H), 2.12 - 1.94 (m, 4H). LCMS (Method A): 561.3 [M+H]+.Example 12: 1-(2-Cvanoacetyl)- / V-((1 S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methylazetidine-3-carboxamide

[0179] To a stirred solution of 2-cyanoacetic acid (8.5 mg, 0.10 mmol, CAS 372-09-8), HOBt (18 mg, 0.14 mmol), EDCI (26 mg, 0.14 mmol) and triethylamine (38 pL, 0.27 mmol) in THF (0.5 mL) was added A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methylazetidine-3-carboxamide TFA salt (Intermediate 52; 50 mg, 91 pmol) and the mixture was stirred at RT for 3 h. The mixture was diluted with water, then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC (PrincetonSFC 2-Ethylpyridine, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% MeOH modifier). Chiral purification by preparative SFC (Chiralpak®-AS-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) to provide the title compound (11 mg) as Peak 1.1H NMR (400 MHz; DMSO-d6) 5: 8.01 (br s, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 7.18 (dd, 1 H), 7.02 (dd, 1 H), 6.55 (d, 1 H), 6.37 (q, 1 H), 4.38 - 4.05(m, 4H), 3.98 - 3.85 (m, 2H), 3.78 - 3.72 (m, 2H), 3.48 - 3.38 (m, 2H), 2.92 - 2.81 (m, 5H). LCMS (Method H): 540.2 [M+H]+.Example 13: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1-imino-A / -methylhexahvdro- thiopyran-4-carboxamide 1-oxide - Diastereomer 1Example 14: / V-((1S)-1-(5-((4,5-Dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1- oxide - Diastereomer 2

[0180] To a solution of Benzyl (4-(((1 S)-1-(5-((4,5-dichloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-1-oxidotetrahydro-2 / 7-1A6- thiopyran-1-ylidene)carbamate (Intermediate 56; 0.50 g, 0.44 mmol) in MeCN (1.8 mL) was added trimethylsilyl iodide (1.32 g, 6.58 mmol) and DIPEA (1.15 mL, 6.58 mmol) and the mixture was stirred at RT for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0-30% MeOH in DCM). Chiral purification was carried out by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% MeOH / MeCN 1:1 modifier) to provide Example 13 (12 mg) as Peak 2 and Example 14 (23 mg) as Peak 4. Example 13:1H NMR (400 MHz; DMSO-d6) 5: 8.04 - 7.99 (m, 1H), 7.44 (d, 1 H), 7.25 (d, 1H), 7.14 (d, 1H), 7.08 - 7.01 (m, 1H), 6.59 - 6.52 (m, 1 H), 6.38 (q, 1 H), 4.38 - 4.30 (m, 1H), 3.49 - 3.35 (m, 4H), 3.18 - 3.03 (m, 4H), 3.00 (s, 3H), 2.93 -2.82 (m, 2H), 2.10 - 1.84 (m, 4H). LCMS (Method A): 549.3 [M+H]+. Example 14:1H NMR (400 MHz; DMSO-d6) 5: 8.04 - 7.99 (m, 1H), 7.44 (d, 1H), 7.25 (d, 1H), 7.14 (d, 1 H), 7.08 - 7.01 (m, 1H), 6.59 - 6.52 (m, 1H), 6.38 (q, 1 H), 4.38 - 4.30 (m, 1 H), 3.49 - 3.35 (m, 4H), 3.14 - 3.00 (m, 7H), 2.93 - 2.82 (m, 2H), 2.05 - 1.88 (m, 4H). LCMS (Method A): 549.3 [M+H]+.Example 15: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide -Diastereomer 1Example 16: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-A / -methyl-1-(methylsulfonyl)azetidine-3-carboxamide -Diastereomer 2

[0181] Prepared in an analogous manner to Example 4 using Intermediate 23 (0.10 g, 0.23 mmol), 1-(methylsulfonyl)-3-azetidinecarboxylic acid (63 mg, 0.35 mmol, CAS 1219828-27-9), T3P® (50% in THF, 1.39 mL, 2.33 mmol) in pyridine (0.3 mL) at RT for 2 h. Purified by flash chromatography (silica gel, 0-80% EtOAc in hexane). Chiral purification was carried out by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% MeOH modifier) to provide Example 15 (13 mg) as Peak 1 and Example 16 (13 mg) as Peak 2. Example 15:1H NMR (400 MHz; DMSO-d6) 6: 8.04 - 8.00 (m, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 7.19 (d, 1 H), 7.08 - 7.01 (m, 1 H), 6.60 - 6.54 (m, 1 H), 6.38 (q, 1 H), 4.38 - 4.30 (m, 1 H), 4.13 - 4.02 (m, 3H), 3.98 (dt, 1 H), 3.92 - 3.82 (m, 1 H), 3.45 - 3.35 (m, 2H), 3.01 - 2.99 (m, 3H), 2.92 - 2.82 (m, 5H). LCMS (Method H): 551.2 [M+H]+. Example 16:1H NMR (400 MHz; DMSO- d6) 6: 8.04 - 8.00 (m, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 7.19 (d, 1 H), 7.08 - 7.01 (m, 1 H), 6.60 - 6.54 (m, 1 H), 6.36 (q, 1 H), 4.38 - 4.30 (m, 1 H), 4.13 - 4.02 (m, 3H), 3.98 (t, 1 H), 3.92 - 3.82 (m, 1 H), 3.47 - 3.35 (m, 2H), 3.01 - 2.99 (m, 3H), 2.92 - 2.82 (m, 5H). LCMS (Method H): 551.2 [M+H]+.Example 17: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)- / V-methyl-1-(oxetane-2-carbonyl)azetidine-3-carboxamide - Diastereomer 1Example 18: A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)- / V-methyl-1-(oxetane-2-carbonyl)azetidine-3-carboxamide - Diastereomer 2

[0182] Prepared in an analogous manner to Example 4 using Intermediate 52 (0.20 g, 0.32 mmol), oxetane-2-carboxylic acid (68 mg, 0.63 mmol, CAS 864373-47-7), T3P® (50% in THF, 1.52 mL, 2.58 mmol) and triethylamine (3.04 mL, 21.8 mmol) in DCM (2.2 mL) at RT for 1 h. Purified by flash chromatography (silica gel, 15% MeOH in DCM). Chiral purification was carried out by preparative SFC (Chiralpak®-IC, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% (10 mM NH4HCO3 in MeOH) modifier) to provide Example 17 (15 mg) as Peak 2 and Example 18 (11 mg) as Peak 4. Example 17:1H NMR (400 MHz; DMSO-d6) 6: 8.01 (br s, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 7.19 (d, 1 H), 7.08 - 7.01 (m, 1 H), 6.60 - 6.54 (m, 1 H), 6.41 - 6.33 (m, 1 H), 5.13 (q, 1 H), 4.59 - 4.31 (m, 4H), 4.26 - 4.08 (m, 2H), 3.99 - 3.86 (m, 2H), 3.48 - 3.36 (m, 2H), 2.92 - 2.73 (m, 6H), 2.69 - 2.62 (m, 1 H). LCMS (Method H): 557.2 [M+H]+. Example 18:1H NMR (400 MHz; DMSO-d6) 6: 8.04 - 8.00 (m, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 7.19 (dd, 1 H), 7.03 (dd, 1 H), 6.60 - 6.54 (m, 1 H), 6.41 - 6.33 (m, 1 H), 5.13 (dd, 1 H), 4.59 - 4.31 (m, 4H), 4.26 - 4.08 (m, 2H), 4.01 - 3.86 (m, 2H), 3.48 - 3.36 (m, 2H), 2.92 - 2.73 (m, 6H), 2.69 - 2.62 (m, 1 H). LCMS (Method H): 557.2 [M+H]+.Example 19: (3S)-A / -((1S)-1-(6-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-A / -methyl-5-oxopyrrolidine-3- carboxamide

[0183] Prepared in an analogous manner to Example 4 using Intermediate 58 (0.30 g, 0.71 mmol), (3S)-5-oxopyrrolidine-3-carboxylic acid (0.18 g, 1.43 mmol, CAS 30948-17-5)and T3P® (50% in EtOAc, 4.25 mL, 7.13 mmol) in pyridine (0.5 mL) at RT for 2 h. Purified by flash chromatography (silica gel, 5-10% MeOH in DCM). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% (10 mM NH4HCO3 in MeOH) modifier) to provide the title compound (61 mg) as Peak 2.1H NMR (400 MHz; DMSO-de) 6: 8.08 - 8.01 (m, 1 H), 7.66 (s, 1 H), 7.48 - 7.33 (m, 2H), 7.24 (d, 1 H), 7.11 (d, 1 H), 6.54 (d, 1 H), 6.37 (q, 1 H), 4.72 - 4.64 (m, 1 H), 3.78 - 3.68 (m, 1 H), 3.56 (dd, 1 H), 3.40 - 3.35 (m, 1 H), 3.34 - 3.32 (m, 2H), 2.92 - 2.83 (m, 5H), 2.39 - 2.32 (m, 2H). LCMS (Method A): 485.3 [M+H]+.Example 20: (3R)-A / -((1 S)-1 -(5-((5-Chloro-4-f I uoro-2,3-di hydro-1 H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methyl-5-oxopyrrolidine-3- carboxamide

[0184] Prepared in an analogous manner to Example 4 using Intermediate 29 (0.10 g, 0.24 mmol), (3R)-5-oxopyrrolidine-3-carboxylic acid (77 mg, 0.60 mmol, CAS 428518-37- 0) and T3P® (50% in EtOAc, 1.42 mL, 2.38 mmol) in pyridine (0.2 mL) at RT for 3 h. Purified by flash chromatography (silica gel, 5-10% MeOH in DCM) then preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier). Chiral purification by preparative SFC (Chiralpak®- IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide the title compound (26 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 6: 8.05 - 8.01 (m, 1 H), 7.65 (s, 1 H), 7.37 (dt, 1 H), 7.14 (dd, 2H), 7.09 - 7.01 (m, 1 H), 6.55 (d, 1 H), 6.38 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.76 - 3.67 (m, 1 H), 3.49 - 3.35 (m, 5H), 2.96 (s, 3H), 2.89 - 2.81 (m, 2H), 2.35 - 2.24 (m, 1 H). LCMS (Method A): 485.3 [M+H]+.idin-5-vl)-2,2,2-trifluoroethvl)-A / -i-2H-thiopvran-4-carboxamide 1,1 -dioxide

[0185] Prepared in an analogous manner to Example 4 using Intermediate 63 (0.20 g, 0.49 mmol), tetrahydro-2 / 7-thiopyran-4-carboxylic acid 1 ,1-dioxide (0.26 g, 1.48 mmol,CAS 64096-87-3) and T3P® (50% in EtOAc, 4.0 mL, 6.70 mmol) in pyridine (0.7 mL) at 60 °C for 4 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-IC, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% MeOH modifier) to provide the title compound (20 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.34 (br s, 2H), 7.92 (d, 1 H), 7.35 - 7.18 (m, 3H), 6.41 (q, 1 H), 4.67 - 4.58 (m, 1 H), 3.33 - 3.05 (m, 7H), 2.98 (s, 3H), 2.95 - 2.84 (m, 2H), 2.13 - 1.94 (m, 4H). LCMS (Method C): 517.4 [M+H]+.Example 22: / V-(1-(2-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyrimidin- 5-yl)-2,2,2-trifluoroethyl)- / V-methyltetrahvdro-2H-thiopyran-4-carboxamide 1,1- dioxide

[0186] Prepared in an analogous manner to Example 4 using Intermediate 68 (0.15 g, 0.35 mmol), tetrahydro-2 / 7-thiopyran-4-carboxylic acid 1 ,1-dioxide (0.19 g, 1.06 mmol, CAS 64096-87-3) and T3P® (50% in EtOAc, 2.08 mL, 3.52 mmol) in pyridine (0.1 mL) at 60 °C for 4 h. Purified by flash chromatography (silica gel, 0-70% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-IC, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% (10 mM NH4HCO3 in MeOH) modifier) to provide the title compound (26 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.35 (br s, 2H), 7.97 (d, 1 H), 7.36 (d, 1 H), 7.09 (d, 1 H), 6.41 (q, 1 H), 4.73 - 4.67 (m, 1 H), 3.40 - 3.35 (m, 1 H), 3.33 - 3.05 (m, 6H), 2.98 - 2.90 (m, 5H), 2.13 - 1.94 (m, 4H). LCMS (Method A): 535.2 [M+H]+.Example 23: A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-imino- / V-methylhexahydro-1A6- thiopyran-4-carboxamide 1 -oxide - Diastereomer 1Example 24: A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-imino- / V-methylhexahydro-1A6- thiopyran-4-carboxamide 1 -oxide - Diastereomer 2

[0187] Prepared in an analogous manner to Example 13 / 14 using Intermediate 69 (0.70 g, 0.57 mmol), trimethylsilyl iodide (1.70 g, 8.50 mmol) and DIPEA (1.48 mL, 8.50 mmol) in MeCN (2.8 mL) at RT for 3 h. Purified by flash chromatography (silica gel, 0-10% MeOH in DCM). Chiral purification was carried out by preparative SFC (Chiralpak®-IC, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% (10 mM NH4HCO3 in MeOH) modifier) to provide Example 23 (50 mg) as Peak 2 and Example 24 (8 mg) as Peak 4. Example 23:1H NMR (400 MHz; DMSO-d6) 5: 8.05 - 8.01 (m, 1 H), 7.37 (t, 1 H), 7.13 (t, 2H), 7.09 - 7.01 (m, 1 H), 6.59 - 6.52 (m, 1 H), 6.39 (q, 1 H), 4.38 - 4.31 (m, 1 H), 3.71 (s, 1 H), 3.45 - 3.35 (m, 2H), 3.18 - 3.00 (m, 7H), 2.89 - 2.82 (m, 2H), 2.68 (s, 1 H), 2.04 - 1.89 (m, 4H). LCMS (Method C): 533.4 [M+H]+. Example 24:1H NMR (400 MHz; DMSO-d6) 5: 8.05 - 8.01 (m, 1 H), 7.37 (t, 1 H), 7.13 (dd, 2H), 7.09 - 7.01 (m, 1 H), 6.59 - 6.52 (m, 1 H), 6.38 (q, 1 H), 4.38 - 4.31 (m, 1 H), 3.49 (s, 1 H), 3.45 - 3.35 (m, 2H), 3.18 - 3.02 (m, 4H), 3.00 (s, 3H), 2.89 - 2.82 (m, 2H), 2.68 (s, 1 H), 2.04 - 1.86 (m, 4H). LCMS (Method C): 533.3 [M+H]+.Example 25: A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-1-imino-A / -methylhexahydro-1A6- thiopyran-4-carboxamide 1 -oxide - Diastereomer 1Example 26: A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-1-imino-A / -methylhexahydro-1A6- thiopyran-4-carboxamide 1 -oxide - Diastereomer 2

[0188] Prepared in an analogous manner to Example 13 / 14 using Intermediate 70 (0.33 g, 0.41 mmol), trimethylsilyl iodide (1.22 g, 6.08 mmol) and DIPEA (1.06 mL, 6.08 mmol) in MeCN (2.3 mL) at RT for 3 h. Purified by flash chromatography (silica gel, 0-100% EtOAcin hexane). Chiral purification was carried out by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% (10 mM NH4HCO3 in MeOH) modifier) to provide Example 25 (26 mg) as Peak 2 and Example 26 (18 mg) as Peak 4. Example 25:1H NMR (400 MHz; DMSO-d6) 6: 8.10 - 8.00 (m, 1H), 7.42-7.32 (m, 2H), 7.29-7.22 (m, 1H), 7.11 (m, 1H), 6.57-6.52 (m, 1H), 6.38 (q, 1H), 4.71 - 4.63 (m, 1H), 3.73 - 3.70 (m, 1H), 3.40 - 3.35 (m, 1H), 3.33 - 3.28 (m, 1H), 3.15-2.98 (m, 5H), 2.92-2.82 (m, 5H), 2.04 - 1.91 (m, 4H). LCMS (Method H): 533.3 [M+H]+. Example 26:1H NMR (400 MHz; DMSO-d6) 5: 8.10-8.00 (m, 1H), 7.42- 7.32 (m, 2H), 7.29 - 7.22 (m, 1 H), 7.20 - 6.93 (m, 2H), 6.58 - 6.52 (m, 1 H), 6.37 (q, 1 H), 4.71 -4.63 (m, 1H), 3.40-3.35 (m, 1H), 3.33-3.10 (m, 6H), 2.93-2.82 (m, 5H), 2.04- 1.91 (m, 4H). LCMS (Method H): 533.3 [M+H]+.Example 27: A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyrimidin- 5-yl)-2,2,2-trifluoroethyl)-1-imino-A / -methylhexahvdro-1A6-thiopyran-4-carboxamide 1 -oxide - Diastereomer 1

[0189] Prepared in an analogous manner to Example 13 / 14 using Intermediate 71a (0.15 g, 0.22 mmol), trimethylsilyl iodide (0.98 g, 4.43 mmol) and DIPEA (0.77 mL, 4.43 mmol) in MeCN (4.6 mL) at RT for 1 h. Chiral purification was carried out by preparative SFC (Chiralpak®-IK, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2with 35% (10 mM NH4HCO3 in 1:1 MeCN I MeOH) modifier) to provide the title compound (15 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.35 (br s, 2H), 7.97 (d, 1H), 7.36 (t, 1H), 7.10 (d, 1H), 6.42 (q, 1H), 4.75-4.67 (m, 1H), 3.73-3.70 (m, 1H), 3.40-3.35 (m, 1H), 3.33-3.28 (m, 1H), 3.15-2.93 (m, 10H), 2.03- 1.93 (m, 4H). LCMS (Method C): 534.4 [M+H]+.Example 28: A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin- 5-yl)-2,2,2-trifluoroethyl)-1-imino-A / -methylhexahydro-1A6-thiopyran-4-carboxamide 1 -oxide - Diastereomer 2

[0190] Prepared in an analogous manner to Example 13 / 14 using Intermediate 71b (0.21 g, 0.30 mmol), trimethylsilyl iodide (1.32 g, 5.99 mmol) and DIPEA (1.04 mL, 5.98 mmol) in MeCN (5 mL) at RT for 1 h. Chiral purification was carried out by preparative SFC (Chiralpak®-IK, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide the title compound (10 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.34 (br s, 2H), 7.97 (d, 1 H), 7.36 (t, 1 H), 7.10 (d, 1 H), 6.41 (q, 1 H), 4.75 - 4.67 (m, 1 H), 3.33 - 3.10 (m, 8H), 3.00 - 2.90 (m, 5H), 2.03 - 1.93 (m, 4H). LCMS (Method C): 534.4 [M+H]+.Example 29: A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-A / -methyl-5-oxomorpholine-2- carboxamide

[0191] A solution of terf-Butyl 2-(((1 S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-5-oxomorpholine-4- carboxylate (Intermediate 73; 0.14 g, 0.15 mmol) in DCM (0.5 mL) and TFA (35 pL) was stirred at RT for 4 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with DCM. The combined organics were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0-100% EtOAc in hexane). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% MeOH modifier) to provide the title compound (8.6 mg) as Peak 4.1H NMR (400 MHz; DMSO-d6) 5: 8.16 - 8.00 (m, 2H), 7.44 - 7.34 (m, 2H), 7.28 - 7.24 (m, 1 H), 7.11 (d, 1 H), 6.54 (d, 1 H), 6.27 (q, 1 H), 4.79 - 4.64 (m, 2H), 4.15 (d, 1 H), 4.03 (d, 1 H), 3.50 (dd, 1 H), 3.40 - 3.35 (m, 1 H), 3.30 - 3.25 (m, 2H), 2.96 (s, 3H), 2.92 - 2.84 (m, 2H). LCMS (Method H): 501.3 [M+H]+.Example 30: (1 ,3-c / s)-A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2- yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)-A / -methyl-3- (methylsulfonyl)cyclobutane-l -carboxamide

[0192] Prepared in an analogous manner to Example 4 using Intermediate 68 (0.16 g, 0.33 mmol), (1 ,3-c / s)-3-methanesulfonylcyclobutane-1-carboxylic acid (0.12 g, 0.67 mmol, CAS 1773508-26-1) and T3P® (50% in EtOAc, 1.96 mL, 3.33 mmol) in pyridine (0.2 mL) at RT for 5 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% MeOH modifier) to provide the title compound (15 mg) as Peak 2.1H NMR (400 MHz; DMSO-de) 5: 8.40 - 8.35 (m, 2H), 8.01 - 7.96 (m, 1 H), 7.36 (t, 1 H), 7.09 (d, 1 H), 6.37 (q, 1 H), 4.75 - 4.66 (m, 1 H), 3.98 - 3.87 (m, 1 H), 3.54 - 3.45 (m, 1 H), 3.40 - 3.35 (m, 1 H), 3.29 - 3.26 (m, 1 H), 2.99 - 2.88 (m, 2H), 2.86 (s, 3H), 2.84 (s, 3H), 2.50 - 2.36 (m, 4H). LCMS (Method A): 535.3 [M+H]+.Example 31 : (3S)-A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)- / V-methyl-5-oxopyrrolidine-3- carboxamide

[0193] Prepared in an analogous manner to Example 4 using Intermediate 68 (0.22 g, 0.52 mmol), (3S)-5-oxopyrrolidine-3-carboxylic acid (0.10 g, 0.78 mmol, CAS 30948-17- 5), triethylamine (0.22 mL, 1.55 mmol) and T3P® (50% in EtOAc, 2.95 mL, 19.4 mmol) in DCM (0.5 mL) at RT for 5 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% 10 mM NH4HCO3 in MeOH modifier) to provide the title compound (4.4 mg) as Peak 4.1H NMR (400 MHz; DMSO-d6) 5: 8.42 - 8.36 (m, 2H), 8.02 - 7.97 (m, 1 H), 7.65 (br s, 1 H), 7.36 (t, 1 H), 7.09 (d, 1 H), 6.41 (q, 1 H), 4.75 - 4.67 (m, 1 H), 3.78 - 3.69 (m, 1 H), 3.56 (t, 1 H), 3.40 - 3.35 (m, 1 H), 3.29 - 3.26 (m, 2H), 2.99 - 2.90 (m, 5H), 2.37 (d, 2H). LCMS (Method C): 486.3 [M+H]+.Example 32: A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3- carboxamide

[0194] Prepared in an analogous manner to Example 4 using Intermediate 29 (47 mg, 0.11 mmol), 1-methylsulfonylazetidine-3-carboxylic acid (19 mg, 0.11 mmol, CAS 1219828-27-9), and T3P® (50% in EtOAc, 0.63 mL, 1.06 mmol) in pyridine (0.2 mL) at RT for 16 h. Purified by flash chromatography (silica gel, 60-70% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% ethanol modifier) to provide the title compound (9.1 mg) as Peak 2.1H NMR (400 MHz; DMSO-de) 6: 8.04 - 8.00 (m, 1 H), 7.37 (t, 1 H), 7.25 - 7.17 (m, 1 H), 7.12 (d, 1 H), 7.08 - 7.01 (m, 1 H), 6.59 - 6.52 (m, 1 H), 6.36 (q, 1 H), 4.40 - 4.33 (m, 1 H), 4.13 - 4.01 (m, 3H), 3.97 (t, 1 H), 3.93 - 3.85 (m, 1 H), 3.45 - 3.35 (m, 2H), 3.02 - 2.99 (m, 3H), 2.87 - 2.76 (m, 5H). LCMS (Method A): 535.3 [M+H]+.Example 33: A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)-A / -methyl-1-(methylsulfonyl)azetidine-3- carboxamide

[0195] Prepared in an analogous manner to Example 4 using Intermediate 58 (0.10 g, 0.26 mmol), 1-methylsulfonylazetidine-3-carboxylic acid (70 mg, 0.40 mmol, CAS 1219828-27-9), and T3P® (50% in EtOAc, 1.55 mL, 2.60 mmol) in pyridine (0.1 mL) at RT for 1 h. Purified by flash chromatography (silica gel, 0-80% EtOAc in hexane). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% (10 mM NH4HCO3 in MeOH) modifier) to provide the title compound (24 mg) as Peak 2.1H NMR (400 MHz; DMSO-de) 5: 8.07 - 8.03 (m, 1 H), 7.47 - 7.42 (m, 1 H), 7.36 (t, 1 H), 7.28 - 7.22 (m, 1 H), 7.11 (d, 1 H), 6.56 - 6.52 (m, 1 H), 6.34 (q, 1 H), 4.69 - 4.63 (m, 1 H), 4.13 - 3.96 (m, 4H), 3.93 - 3.84 (m, 1 H), 3.40 - 3.35 (m, 1 H), 3.30 - 3.25 (m, 1 H), 3.02 - 2.99 (m, 3H), 2.92 - 2.83 (m, 2H), 2.76 - 2.73 (m, 3H). LCMS (Method A): 535.3 [M+H]+.

[0196] Prepared in an analogous manner to Example 4 using Intermediate 68 (0.15 g, 0.34 mmol), 1-methylsulfonylazetidine-3-carboxylic acid (93 mg, 0.52 mmol, CAS 1219828-27-9), and T3P® (50% in EtOAc, 2.19 g, 3.44 mmol) in pyridine (0.2 mL) at RT for 1 h. Purified by preparative SFC (Chiralpak®-IE, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 57% CO2with 43% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide the title compound (26 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 6: 8.42 - 8.35 (m, 2H), 8.03 - 7.95 (m, 1 H), 7.36 (t, 1 H), 7.10 (d, 1 H), 6.39 (q, 1 H), 4.74 - 4.66 (m, 1 H), 4.11 (t, 1 H), 4.03 (d, 2H), 3.97 (t, 1 H), 3.91 - 3.82 (m, 1 H), 3.40 - 3.35 (m, 1 H), 3.30 - 3.25 (m, 1 H), 3.02 - 2.87 (m, 5H), 2.80 - 2.76 (m, 3H). LCMS (Method A): 536.2 [M+H]+.Example 35: (1 ,3-trans)-A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methyl-3-(methylsulfonyl)cyclobutane- 1 -carboxamide

[0197] Prepared in an analogous manner to Example 4 using Intermediate 29 (0.20 g, 0.54 mmol), (1 ,3-trans)-3-methanesulfonylcyclobutane-1-carboxylic acid (0.11 g, 0.60 mmol, CAS 2097988-81-1), and T3P® (50% in EtOAc, 0.52 g, 1.63 mmol) in pyridine (2.7 mL) at RT for 16 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.1 % aqueous formic acid with MeCN 50-58% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% 1 :1 MeCN 1 1 PA modifier) to provide the title compound (8.4 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 6: 8.03 - 8.00 (m, 1 H), 7.37 (t, 1 H), 7.25 - 7.10 (m, 2H), 7.02 (dd, 1 H), 6.54 (d, 1 H), 6.37 (q, 1 H), 4.39 - 4.33 (m, 1 H), 3.92 - 3.83(m, 1 H), 3.58 - 3.49 (m, 1 H), 3.45 - 3.35 (m, 2H), 2.95 - 2.92 (m, 3H), 2.87 - 2.81 (m, 5H), 2.66 - 2.53 (m, 4H). LCMS (Method H): 534.3 [M+H]+.Example 36: (3S)-A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)-A / -methyl-6-oxopiperidine-3- carboxamide

[0198] A solution of terf-Butyl (5S)-5-((1-(2-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-2-oxopiperidine-1- carboxylate (Intermediate 77; 0.12 g, 0.19 mmol) in DCM (5 mL) and TFA (0.14 mL) was stirred at RT for 2 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0-5% MeOH in DCM). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% (10 mM NH4HCO3 in 1 :1 MeCN / MeOH modifier) to provide the title compound (26 mg) as Peak 1.1H NMR (400 MHz; DMSO-d6) 6: 8.34 (br s, 2H), 7.97 (d, 1 H), 7.49 (br s, 1 H), 7.36 (t, 1 H), 7.09 (d, 1 H), 6.40 (q, 1 H), 4.75 - 4.66 (m, 1 H), 3.40 - 3.35 (m, 1 H), 3.30 - 3.15 (m, 4H), 3.00 (s, 3H), 2.98 - 2.90 (m, 2H), 2.25 - 2.18 (m, 2H), 1.92 - 1.71 (m, 2H). LCMS (Method A): 500.2 [M+H]+.37: (1 ,3-c / s)- / V-((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1 -carboxamide - Diastereomer 11 -carboxamide - Diastereomer 2

[0199] Prepared in an analogous manner to Example 4 using Intermediate 58 (27 mg, 72 pmol), (1 ,3-c / s)-3-methanesulfonylcyclobutane-1-carboxylic acid (14 mg, 80 pmol, CAS 1773508-26-1), and T3P® (50% in MeTHF, 0.12 mL, 0.20 mmol) in pyridine (0.6 mL) at RT for 17 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.1% aqueous formic acid with MeCN 30-40% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide Example 37 (30 mg) as Peak 1 (31 mg) and Example 38 as Peak 2. Example 37:1H NMR (400 MHz; DMSO-d6) 5: 8.07 - 8.00 (m, 1 H), 7.46 - 7.34 (m, 2H), 7.24 (d, 1 H), 7.11 (d, 1 H), 6.53 (d, 1 H), 6.32 (q, 1 H), 4.72 - 4.63 (m, 1 H), 3.98 - 3.88 (m, 1 H), 3.52 - 3.43 (m, 1 H), 3.40 - 3.35 (m, 2H), 2.90 - 2.86 (m, 5H), 2.79 (s, 3H), 2.49 - 2.38 (m, 4H). LCMS (Method C): 534.3 [M+H]+; Example 38:1H NMR (400 MHz; DMSO-d6) 5: 8.07 - 8.00 (m, 1 H), 7.46 - 7.34 (m, 2H), 7.24 (d, 1 H), 7.11 (d, 1 H), 6.53 (d, 1 H), 6.32 (q, 1 H), 4.72 - 4.63 (m, 1 H), 3.98 - 3.88 (m, 1 H), 3.52 - 3.43 (m, 1 H), 3.40 - 3.35 (m, 2H), 2.90 - 2.86 (m, 5H), 2.79 (s, 3H), 2.49 - 2.38 (m, 4H). LCMS (Method C): 534.3 [M+H]+.Biological AssaysMALT 1 Protease Assay 1

[0200] MALT 1 protease activity was assessed in vitro by measuring the cleavage of a fluorogenic tetrapeptide substrate.

[0201] For a higher sensitivity assay, commercially available FL hMALTI enzyme (Abeam, 1-10 nM) was incubated with substrate (Ac-LVSR-AMC, 100 pM) in reaction buffer comprising 50 mM HEPES (pH7.0), 25 mM KCI, 0.1% (v / v) CHAPS, 1 mM TCEP and 0.7 M sodium citrate.

[0202] Test compounds dissolved in DMSO were dispensed into assay plates (384-well, black, shallow ProxiPlates). 7 pl enzyme solution was added and incubated at room temperature for 30 minutes to allow compound binding to occur. 2 pl substrate solution was then added and the fluorescence (excitation 360nm, emission 460nm) read every 15 minutes using a suitable plate reader. Final assay DMSO concentration was 1%. Linearity over 60 minutes was confirmed, and assay signal was calculated by subtracting raw countsat time 0 from those at 60 minutes. % inhibition was calculated for each well, using no enzyme for 100% inhibition controls and no compound for 0% inhibition controls. IC50 values were calculated using GraphPad Prism using a 4-parameter non-linear regression curve fit.Human IL-2 Release Phenotypic Assay (Assay 2)

[0203] This assay measured the inhibition by MALT1 inhibitors of the IL-2 release from stimulated Jurkat cells, a human immortalized T lymphocyte cell line. IL-2 production from Jurkat cells is regulated by activation of NFKB signalling, which is in turn regulated by MALT 1 protease activity.

[0204] Jurkat cells (clone E6-1 , ATCC) were cultured in RPMI1640 supplemented with 10% (v / v) FBS and 1% (v / v) penicillin / streptomycin (100x liquid stocks). Cells were seeded in 96-well white tissue culture-treated plates (Perkin Elmer) at 50 000 cells / well and incubated overnight at 37°C, 5% CO2. Test compounds in DMSO at half-log dilutions were added to the cells and incubated for 30 mins. Final DMSO concentration was 0.5%. Cells were then stimulated with 200 ng / mL PMA + 300 ng / mL ionomycin and incubated for 48 hours. IL-2 present in the supernatant was then measured by ELISA according to the kit instructions (ELISA MAX Deluxe Set Human IL-2, BioLegend). % inhibition was calculated for each well, using 30 pM of the commercially available MALT1 inhibitor, MLT-748, for 100% inhibition controls and no compound for 0% inhibition controls. IC50 values were calculated using GraphPad Prism using 4-parameter non-linear regression curve fit.

[0205] The results of testing the Example compounds in the two in vitro assays described above are shown in Table 1.Table 1 : MALT1 assay dataIL-2 Release PK / PD Model

[0206] Female C57BL / 6 mice at approx. 6 weeks of age are allocated into groups based on body weight, and orally dosed with compound at time T -1 hr, in a vehicle comprising 20% HPBCD (w / v), 0.5% Tween 80 (v / v) and 10% (v / v) N,N-di-methyl acetamide in saline, at a volume of 10 mL / kg. One hour later, at TO, they are challenged with an intravenous injection of anti-CD3 antibody (Ultra-LEAF™, #100340 Biolegend), appropriately diluted in sterile PBS to dose 10 pg / mouse in a volume of 100 pL. 4 hours after aCD3 challenge the mice are anaesthetized and terminal blood samples collected from the carotid artery. A 20 pL blood sample is transferred to an EDTA tube, then diluted 1:1 with water and frozen at -20°C until subsequent bioanalysis by LC-MS / MS. The remaining blood samples are allowed to clot for 30 minutes, centrifuged to separate serum, snap frozen and stored at - 80°C until IL-2 analysis by ELISA (Mouse IL-2 DuoSet ELISA, R&D Systems). IL-2 concentration in the serum is calculated by interpolation from a standard curve. Statisticalanalysis (ordinary one-way ANOVA and Dunnett’s multiple comparison) is performed using GraphPad Prism.

Claims

CLAIMS1. A compound selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)- / V-methyl-1-(methylsulfonamido)cyclopropane-1 -carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-2-oxohexahydropyrimidine-5-carboxamide; / V-((1 S)-1-(5-((5-Chloro-4-(difluoromethyl)-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin- 2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1- dioxide;(1 ,3-c / s)- / V-((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1 -carboxamide;A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)- / V-methyl-2-oxohexahydropyrimidine-5-carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-5-oxomorpholine-2-carboxamide;(1 ,3-c / s)- / V-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin- 2-yl)-2,2,2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1-carboxamide;(1 ,3-trans)-N1-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / 1,A / 3-dimethylcyclobutane-1 ,3- dicarboxamide;(3S)- / V-((1 S)-1-(6-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)-A / -methyl-6-oxopiperidine-3-carboxamide;A / -(1-(2-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)- / V-methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide; / V-(1-(6-((5-Bromo-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridazin-3-yl)-2,2,2- trifluoroethyl)- / V-methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;1-(2-Cyanoacetyl)- / V-((1 S)-1-(5-((4,5-dichloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methylazetidine-3-carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1-oxide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;A / -((1 S)-1-(5-((4,5-Dichloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V-methyl-1-(oxetane-2-carbonyl)azetidine-3-carboxamide;(3S)-A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)- / V-methyl-5-oxopyrrolidine-3-carboxamide;(3 / ?)-A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)- / V-methyl-5-oxopyrrolidine-3-carboxamide;A / -(1-(2-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)-A / -methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)-A / -methyltetrahydro-2 / 7-thiopyran-4-carboxamide 1 ,1 -dioxide;A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1- oxide;A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1- oxide;A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2- trifluoroethyl)-1-imino- / V-methylhexahydro-1A6-thiopyran-4-carboxamide 1-oxide;A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)- / V-methyl-5-oxomorpholine-2-carboxamide;(1 ,3-c / s)- / V-(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5- yl)-2,2,2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1-carboxamide;(3S)-A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2.2.2-trifluoroethyl)- / V-methyl-5-oxopyrrolidine-3-carboxamide;A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;A / -((1 S)-1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;A / -((1 S)-1-(2-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)-2,2,2-trifluoroethyl)- / V-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;(1 ,3-trans)-A / -((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-A / -methyl-3-(methylsulfonyl)cyclobutane- 1-carboxamide;(3S)-A / -(1-(2-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyrimidin-5-yl)- 2,2,2-trifluoroethyl)- / V-methyl-6-oxopiperidine-3-carboxamide; and(1 ,3-c / s)- / V-((1 S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin- 3-yl)-2,2,2-trifluoroethyl)- / V-methyl-3-(methylsulfonyl)cyclobutane-1-carboxamide.

2. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in therapy.

4. A pharmaceutical composition according to claim 2 for use in therapy.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or disorders mediated by MALT1.

6. A pharmaceutical composition according to claim 2 for use in the treatment of diseases or disorders mediated by MALT1.

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large 13- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma,rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft- versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

8. A pharmaceutical composition according to claim 2 for use in the treatment of nonHodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograftrejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody- mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

9. A method of treating a disease or disorder mediated by MALT1 , said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

10. A method of treating a disease or disorder mediated by MALT1 , said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to claim 2.

11. A method of treating non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout,organ or transplant rejection, chronic allograft rejection, acute or chronic graft- versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

12. A method of treating non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft- versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitissyndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to claim 2.

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